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luminescent detection of natural amino acids by organometallic systems
Accepted Manuscript Title: Fluorescent/Luminescent Detection of Natural Amino Acids by Organometallic Systems Author: Jing Wang Hai-Bo Liu Zhangfa Tong Chang-Sik Ha PII: DOI: Reference:
S0010-8545(15)00177-0 http://dx.doi.org/doi:10.1016/j.ccr.2015.05.008 CCR 112079
To appear in:
Coordination Chemistry Reviews
Received date: Revised date: Accepted date:
25-1-2015 4-4-2015 11-5-2015
Please cite this article as: J. Wang, H.-B. Liu, Z. Tong, C.-S. Ha, Fluorescent/Luminescent Detection of Natural Amino Acids by Organometallic Systems, Coordination Chemistry Reviews (2015), http://dx.doi.org/10.1016/j.ccr.2015.05.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Fluorescent/Luminescent Detection of Natural Amino
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Acids by Organometallic Systems
School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004,
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Jing Wang,a Hai-Bo Liua*[email protected], Zhangfa Tonga, Chang-Sik Hab*[email protected]
People's Republic of China
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Department of Polymer Science and Engineering, Pusan National University, Busan 609-735, Korea
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Highlights
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luminescent organometallic systems
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A wide variety of approaches in designing amino acid (AA) sensors based on fluorescent and
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Sensing mechanisms employed by organometallic systems for fluorescent and luminescent AA sensing Different roles of metals and organic parts played in selective AA sensing Chiral recognition to discriminate AA enantiomers (i.e., D and L) Pattern recognition to distinguish a range of AAs simultaneously
ABSTRACT
In comparison with other detection technologies, fluorescence/luminescence technology has become a powerful tool owing to its advantageous features including simplicity, low cost, high sensitivity, quick response time, easy sample preparation, noninvasive and nondestructive nature, etc. Due to the 1 Page 1 of 184
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important roles played by 20 natural amino acids in living systems, this review focuses on recent contributions
(from
the
year
2000
until
July
2014)
regarding
the
development
of
fluorescent/luminescent chemosensors and chemodosimeters to detect specific AAs, as well as chiral recognition to discriminate AA enantiomers (i.e., D and L), and pattern recognition to distinguish a
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range of AAs simultaneously based on fluorescent/luminescent organometallic systems, which include
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organic–metal complexes and hybrid organic–metal nanoparticles/nanoclusters.
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and chemodosimeters; chiral recognition; pattern recognition
CONTENTS
4
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ABBREVIATIONS ABSTRACT
6 6
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1. Introduction
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2. Detection Mechanisms
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Keywords: Amino acids; fluorescent and luminescent detection; organometallic systems; chemosensors
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2.1. Binding Site-Signaling Subunit Approach
7
2.2. Displacement Approach
8
2.3. Chemodosimeter Approach
8
3. The Advantages of Metal and Organic Combination 4. Organic-Metal Complexes
4.1. Small Molecule-Metal Complexes 4.1.1. Using Binding Site-Signaling Subunit Approach
9 10 10 10
4.1.1.1. Zinc Complexes
10
4.1.1.2. Copper Complexes
12
4.1.1.3. Iridium Complexes
13
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4.1.1.4. Others
14 16
4.1.2.1. Zinc Complexes
16
4.1.2.2. Copper Complexes
17
4.1.2.3. Silver Complexes
21
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4.1.2. Using Displacement Approach
4.1.2.4. Mercury Complexes
4.1.2.5. Others
24 25
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4.1.3. Using Chemodosimeter Approach
25 26
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4.1.3.1. Platinum Complexes
4.1.3.3. Ruthenium Complexes
23
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4.1.2.4.2. Chemosensing of other AAs
4.1.3.2. Iridium Complexes
21
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4.1.2.4.1. Chemosensing of Cys
21
28
31
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4.2. Polymer-Metal Complexes
30
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4.1.3.4. Copper Complexes
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4.2.1. Using Displacement Approach 4.2.1.1. Copper Complexes
31 31
4.2.1.1.1. Introducing Cu2+ binding sites into the polymer side chains
31
4.2.1.1.2. Using the ensembling strategy of DNA and Cu2+
4.2.1.2. Mercury Complexes
33 34
4.2.1.2.1. Using the ensembling strategy of DNA and Hg2+
34
4.2.1.2.2. Using the formation and dissociation strategy of polymer-Hg2+ complex 36 4.2.1.3. Silver Complexes 4.2.1.3.1. Introducing Ag+ binding sites into the polymer backbone
36 36
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4.2.1.3.2. Using the ensembling strategy of DNA and Ag+
37
4.2.1.4. Cobalt Complexes
38
4.2.1.4.1. Introducing Co2+ binding sites into the polymer side chains
38
4.2.2. Using Chemodosimeter Approach
38 38
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4.2.2.1. Iridium Complexes 4.2.2.2. Metal-Organic Frameworks (MOF)
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5. Hybrid Organic-Metal Nanoparticles/Nanoclusters
39
40
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5.1. Small Molecule-Functionalized Metal Nanoparticles/Nanoclusters 40
5.1.2. Using Displacement Approach
40 41
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5.1.1.1. Gold Nanoparticles 5.1.1.2. Quantum Dots
40
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5.1.1. Using Binding Site-Signaling Subunit Approach
42 42
5.1.2.2. Silver Nanoparticles
43
5.1.2.3. Quantum Dots
43
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5.1.2.1. Gold Nanoparticles/Nanoclusters
5.2. Polymer-Functionalized Metal Nanoparticles/Nanoclusters
45
5.2.1. Using Binding Site-Signaling Subunit Approach
45
5.2.1.1. DNA-Templated Silver Nanoclusters
45
5.2.1.2. DNA-Templated Copper NanoClusters
46
5.2.2. Using Displacement Approach
47
5.2.2.1. Polymer-Templated Gold Nanoparticles/Nanoclusters
47
5.2.2.2. Polymer-Templated Silver Nanoclusters
48
6. Chiral/Enantiomeric Recognition 6.1. Using Binding Site-Signaling Subunit Approach
49 50
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6.1.1. Introducing Chirality into the Binding Site of the Sensor 6.1.1.1.
Introducing
Chirality
into
50 Dansylated
Cyclodextrins
50 52
6.1.1.3. Introducing Chirality into Quantum Dots
52
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6.1.1.2. Introducing Chiral Molecules as Binding Sites
6.2. Using Enantioselective Indicator Displacement Assays
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7. Pattern Recognition 8. Conclusions
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Acknowledgment References
GSH
53 53 54 57 58 59 70
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amino acids
Hcy
homocysteine
glutathione
ET
electron transfer
NPs
nanoparticles
NCs
Tpy
terpyridine
Phen
Trp
tryptophan
Phe
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AAs
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Figure Captions
ABBREVIATIONS
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6.1.2. Labeling Amino Acids Enantiomers with the Fluorescence Indicator
nanoclusters 1, 10-Phenanthroline phenylalanine
His
histidine
Val
valine
Ala
alanine
Pro
proline
Asp
aspartic acid
Glu
glutamic acid
Cys
cysteine
Arg
arginine
ICT
intramolecular charge-transfer
LOD
limit of detection
5 Page 5 of 184
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THF
tetrahydrofuran
LMCT
PBS
phosphate-buffered saline
DMF
PET
photoinduced electron transfer
BINOL
metal-to-ligand charge transfer
dimethylformamide
IFE
DMSO dimethyl sulfoxide
1,1′-bi-naphthol
fluorescence inner filter effect
T
thymine
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MLCT
ligand-to-metal charge transfer
reduced graphene oxide
pba
4-(2-pyridyl)benzaldehyde
acac
acetylacetone
bpy
2, 2’-bipyridine,
FRET
fluorescence resonance energy transfer
Ser
serine
PL
photoluminescence
ECL
DNBS
2, 4-dinitrobenzenesulfonyl
G
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rGO
NIR
near infrared
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d
quantum dots bovine serum albumin
IDA
indicator-displacement assay
MeOH
human serum albumin
dopamine
Leu
leucine
Asn
asparagine
methionine
Ile
isoleucine
glycine
Lys
lysine
Gln
glutamine
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Gly
HSA
mercaptoacetic acid
DA
gold nanorods
Met
MAA
threonine
mercapto propionic acid
GNRs
sodium citrate
Thr
tyrosine
MPA
HEPES
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BSA
Tyr
N-ethylmaleimide
dsDNA double-stranded DNA
cytosine
QDs
guanine
NEM
ssDNA single-stranded DNA C
electrochemiluminescence
methanol
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
6 Page 6 of 184
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1. INTRODUCTION
Amino acids (AAs) are important components in a range of chemical and biological systems. They combine to yield proteins, enzymes, structural elements and many other molecules with biological
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activity. Their role as building blocks in living systems, along with the discovery that the concentration of free AAs is closely related to the metabolism of peptides and proteins in life and various
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physiological processes, has prompted increasing interest in their detection in various fields, such as
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chemistry, biochemistry and clinical chemistry [1-4]. In view of the role played by the 20 natural AAs in daily life [5-17], the development of techniques for sensing and monitoring natural AAs is important
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in the diagnosis and treatment of diseases.
Among the different methods applied to the detection of AAs, fluorescence/luminescence
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spectroscopic techniques, have drawn substantial interest from researchers owing to their advantageous features including simplicity, low cost, high sensitivity, quick response time, easy sample preparation,
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noninvasive and nondestructive nature, real-time analysis, and diverse signal output modes. Natural
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AAs exhibit similar properties because of the special arrangement of their carboxyl and amino groups.
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The key requirement of fluorescent/luminescent approaches to selective and discriminative detection of target AAs are fluorescent/luminescent probes that have the ability to differentially interact with the target AAs in a manner that gives rise to different optical signal outputs. Chemosensors that rely on the coordination are not as selective as preferred because of their relatively low selectivity and the structural similarity of natural AAs [18]. Therefore, the achievement of a selective AA recognition represents a challenge [19-21], a combination of stronger binding sites in a recognition system is an important factor in designing effective AA receptors. However, selective detection of a specific AA without interference from other AAs is difficult. As far as selectivity is concerned, chemodosimeters provide an ideal way to design fluorescent/luminescent probes, in which a significant chemical transformation involving the breaking or formation of several covalent bonds was induced by a specific natural AA. Currently, 7 Page 7 of 184
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organic-metal based fluorescent/luminescent probes are extensively used as one of the most successful strategies [22] for detecting AAs, which however have not been systematically summarized to our knowledge. Although studies on the use of chemosensors for the detection of AAs have been reviewed by Zhou
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and Yoon [21], a large number of important studies on natural AA sensing based on organometallic systems were not discussed in their review. Therefore, we focus particular attention to review the
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literature from 2000 to July 2014, covering the fluorescent/luminescent probing of 20 natural AAs by
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organometallic systems. Other AAs such as homocysteine (Hcy) and glutathione (GSH), as well as derivatives of AAs, were not included in this review. This review provides a reference for those who are
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interested in this growing and exciting research field.
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2. Detection Mechanisms
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2.1. Binding Site-Signaling Subunit Approach
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In the binding site-signaling subunits approach [23-25], the ‘‘binding site” part (receptor) and
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“signaling subunit’’ part (indicator) are linked through a covalent bond, and the interaction of the analytes (such as AAs) with the binding site alters the electronic properties of the signaling subunit, resulting in sensing of the target analytes via color, absorption or emission modulation. The binding between the receptor and analyte is typically labile and reversible, and involves different interactions, including electronic interactions, hydrogen bonding and metal-ligand interactions, etc.
2.2. Displacement Approach
The displacement approach [26] uses binding sites and signaling subunits to form a molecular ensemble through non-covalent interactions. Upon the addition of a specific amino acid (AA), the 8 Page 8 of 184
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indicators are replaced, resulting in a change in their optical properties. This type of supramolecular approach toward sensing is very simple to implement. Furthermore, the sensitivity and selectivity of the assay can be modulated by varying the receptor-indicator ratio or sensing conditions (e.g. pH).
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2.3. Chemodosimeter Approach
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Chemodosimeters [27] are molecular devices that interact with their analytes and yield physically
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measurable signals in an irreversible manner. Conventional chemodosimeters are generally molecular assemblies of receptor and signaling units. In contrast to chemosensors, which respond to the real-time
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concentration of their analytes, chemodosimeters respond to their analytes in a cumulative manner. Compared with chemosensors, chemodosimeters have advantages in terms of selectivity and sensitivity,
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and their cumulative effect plays an important role in the detection of analytes [28].
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3. The Advantages of Metal and Organic Combination
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For detecting AAs, metal ions can play an important role [29]: (1) they can represent the active site for interacting with AAs [30]. They serve as binding sites in the development of AA probes. An obvious requirement for an organic-metal combined system to serve as a binding site is its stability. (2) The interaction between a metal centre and AAs is often a convenient route for achieving strong binding [26]. In this case, AAs can capture metals from organometallic systems and the organic part can be displaced by the AAs. (3) Metal ions can also be used profitably as structural elements for assisting AAs binding without exerting any a direct interaction with AAs [31-32]. Organic-metal complexes have widespread use in molecular recognition [33-34]. Metal ions are positively charged in aqueous solutions but the charge can be manipulated depending on the coordination environment so that a metal complexed by ligands (organic part) can be cationic, anionic 9 Page 9 of 184
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or neutral. Metal complexes have advantageous photophysical properties, such as high stability and relatively long lifetimes compared with those of organic fluorophores. The ligands impart their own functionality and can tune the properties of the overall complex to make it unique compared with those of the individual ligand (organic part) or metal. In addition, metal complexes can be modified easily
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with different functional groups to tune the energy band. The application of metal nanoparticles (NPs) [35-37] in bioanalysis has attracted considerable
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interest because of their remarkable optical, electrical and chemical properties. In particular, ligand-
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protected metal NPs are being explored increasingly as analytical tools in many biological fields. The introduction of organic ligands onto NP surfaces not only provides stability, but also desirable surface
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functionalities. In addition, the recently developed semiconductor quantum dots show great promise as fluorescence probes owing to their improved photophysical properties, including high quantum yield,
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size-tunable narrow emissions and minimal photobleaching compared with conventional organic fluorophores. Because surface-bound electron-rich small organic molecules can transfer electrons
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efficiently to quantum dots, the successful application of this fundamental electron transfer (ET) process
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has been the analysis of a wide range of analytes.
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Combinations of organic functions and metal ions can have advantages, such as tunable, welldefined coordination geometries, and interesting photophysical properties, such as long emission lifetimes (100 ns to ms), tunable emission wavelengths, high photostability and large Stokes shifts (hundreds of nm), as well as alternative binding interactions and pathways.
4. Organic-Metal Complexes
In the process of the design of fluorescent/luminescent probes, based on organic-metal complexes, proper constitutional components, such as fluorophores, metals and binding units must be chosen to construst the target AA chemosensors/chemodosimeters. With different metal coordination sites and 10 Page 10 of 184
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fluorophores fitted onto the organic-metal complexes, varied interactions or binding modes occur. For example, the fluorescent ligands, such as terpyridine (Tpy), 1, 10-Phenanthroline (Phen), and nonfluorescent ligands, such as crown ethers, calixarenes, bipyridine, etc. are frequently used as metal coordination sites; the fluorophores, such as pyrene, dansyl, rhodamine, etc. are commonly used as the
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signaling reporters. In the following sections, we will indicate the designing rules that have been applied in the practical examples for gaining metal-organic combinational fluorescent/luminescent
4.1. Small Molecule-Metal Complexes
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4.1.1. Using Binding Site-Signaling Subunit Approach
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chemosensors or chemodosimeters.
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In this approach, the metal ion center had been developed as binding sites of AAs due to the
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4.1.1.1. Zinc Complexes
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metal center and AAs.
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covalent or noncovalent interactions, such as electronic and hydrogen interactions, etc. between the
The zinc ion center have been used as the binding sites due to the electronic interaction between Zn2+ and AAs. In 2001, Fabbrizzi et al. reported a zinc complex of tetramine 1 with anthracene as signaling reporter for the sensing of AAs (Figure 1) [38]. Although only tryptophan (Trp) induced fluorescence quenching of [Zn(1)]2+ due to Zn2+-carboxylate coordinative interaction as well as ET process from indole (donor) to anthracene fragment (acceptor), among all the natural AAs examined, the presence of phenylalanine (Phe) interfered with the sensitivity of the complex [Zn(1)]2+ toward Trp. Zhang et al. applied complex 2 (Figure 1) to signal histidine (His) in methanol (MeOH)/H2O cosolvents as well as in aqueous solution using the optode membrane [39]. The zinc centre acted as an 11 Page 11 of 184
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acceptor, whereas the transduction signal for the recognition process was realized through the pyrene excimer fluorescence. Although 2 could interact with other AAs and anions, the large difference in the fluorescence response of 2 to AAs and anions means that this sensor meets the selectivity requirements of a His assay in physiological fields.
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Nag et al. reported that the zwitterionic form of alanine (Ala), His, valine (Val) and proline (Pro), RN+H2…CO2-, were quite effective in binding with the [Zn2(3)]2+ fluorophore (Figure 2) [40] through
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their carboxylate unit with equilibrium constant values of 2.5(3)×105 for Ala, 3.1(2)×105 for His,
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4.4(4)×105 for Val and 8.0(5)×105 for Pro.
The compound 4 showed stronger fluorescence emission, as compared with 5 that lacks triazol part
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(Figure 2) [41]. The Zn2+ complex of 4, [Zn(4)(H2O)3]2+, interacted with L-aspartic acid (Asp) and Lglutamic acid (Glu) due to the coordination of the AAs to the Zn2+ ion, resulting in an increase in
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fluorescence emission with a hypsochromic shift. The binding constants calculated for the AAs were as follows; Ka (L-Asp)=1×104 M-1, Ka (L-Glu)=5.5×103 M-1. However, that study did not provide
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information on the selectivity of the 4-Zn2+ complex toward AAs.
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Recently, a modular approach was developed for fluorescence sensing of AAs to improve water
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solubility of receptors and their binding interactions to free AAs, in which Zn2+ complexes of Tpy derivatives and crown ethers are used as modules for coordination with carboxylates or Lewis basic side chains and π-containing side chains or Lewis acidic groups, respectively. The ammonium group of the zwitterionic AAs can coordinate with [Zn(6)]2+ because of the crown ether subunit in complex [Zn(6)]2+, thus providing a stronger binding affinity toward L-AAs, such as L-aspartate (K = 4.5×104 M−1) and Lcysteine (Cys) (K = 2.5×104 M−1), as compared with [Zn(7)]2+ without crown ether. The binding affinity of [Zn(6)]2+ with L-AAs is highly associated with the coordinating abilities of the side chain on AAs (Figure 2) [42]. On the other hand, it is difficult to differentiate L-aspartate from L-Cys. In addition, the interference of other AAs on the sensitivity of the receptor to a specific AA was not examined. Zn(8) (Figure 3) senses arginine (Arg) by blocking intramolecular charge transfer (ICT) from the crown ether 12 Page 12 of 184
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moiety to the Tpy-Zn2+ moiety, with an association constant Kass of 1.78×104 M−1 by forming a 1:1 complex [43]. By comparison, Zn(9) without the crown ether moiety and compound 9 exhibited negligible response upon the addition of Arg, showing that the crown ether moiety and Tpy-Zn2+ complex moiety in the receptor Zn(8) play important roles in Arg recognition. The Zn2+ complex of 10
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(Figure 4) can distinguish His from Cys, as well as other AAs [44]. In addition, 10-Zn2+ can also distinguish His from other imidazole derivatives. When treated with various AAs, the fluorescence
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enhancement of 10-Zn2+ solution (2.0×10−5 M/5.0×10−5 M) was observed only in the presence of His,
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accompanied by the formation of a white milky precipitate, which was a polymer formed through the interaction of the entire His molecule with the complex 10-Zn2+. The precipitate exhibits stronger
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fluorescence than the soluble components, which can be attributed to the significantly increased structural rigidity of the solid-state polymeric structures. By comparison, 11-Zn2+ and 12-Zn2+ showed
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4.1.1.2. Copper Complexes
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Insert Table 1 and Figures 1-4 Herein
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no fluorescence response to His and other AAs.
Following the binding site-signaling subunit approach, copper complexes have been successfully applied in detecting His, in which His acted as an additional ligand through coordinating to the copper ion center. For instance, complex 13 (Figure 5), which consists of Tpy and CuCl2, was used for L-His detection [45]. L-His was coordinated with a more basic imidazole nitrogen (vs. the carbonyl group) and an α-amine group to the Cu2+ center of complex 13 by forming a 1:1 complex between 13 and L-His, with an association constant of 8.94×103 M−1. Upon coordination of L-His with 13, the Cu2+ center became more electron-rich, which makes the electron or energy transfer from the excited state of Tpy more difficult, resulting in significant fluorescence enhancement of Tpy. 13 Page 13 of 184
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The Cu2+ complex of 14, (Cu2+)2(14) [46], showed selective detection of His and Cys through different recognition pathways (Figure 6). When Cys or His is added to (Cu2+)2(14), the fluorescence emission increased linearly in the range of 90 mM to 2,800 mM for Cys and 200 mM to 3,200 mM for His. In the presence of excess Cys and His, Cu2+ was removed from the (Cu2+)2(14) and (Cu2+-His)2(14)
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was formed, respectively. The binding constant between (Cu2+)2(14) and His was (1.4±0.03)×104 M−2. (Cu2+)2(14) was used for the quantitative estimation of total [Cys]+[His] present in human blood plasma.
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Qian et al. reported that the Cu2+ complex of 15 (Figure 6) could discriminate His from other α-AAs
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with high selectivity and sensitivity [47]. Upon addition of His (0 µM to 80 µM), the fluorescence of 15 at 537 nm that was quenched by Cu2+ was recovered, along with the enhancement of fluorescence
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intensity at 476 nm. In this process, His acted as a chelating ligand binding to Cu2+, which changed the mode of Cu2+ that was coordinated with the pyridine N atom of 15 and reduced the charge density in the
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Cu2+ ion, resulting in the enhanced ICT effect and blockage of the ligand-to-metal charge transfer
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Insert Figures 4-6 Herein
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(LMCT).
4.1.1.3. Iridium Complexes
In the sensing of AAs based on iridium complex, the iridium iron center acted as binding sites through covalent interactions between iridium and AAs. As observed by Wong et al. [48], the iridium complex [Ir(16)]+ (Figure 7) showed enhanced fluorescence upon coordination with His through covalent attachment with the imidazole moiety of His via a ligand substitution reaction with the H2O ligand. The fluorescence intensity of [Ir(16)]+ (50 μM) showed up to 180-fold enhancement at a ratio of [His]/[Ir(16)]+ ≥ 4:1 without interference from other natural AAs. Chen and coworkers used iridium complex 17 (Figure 8) for the time-dependent detection of Cys 14 Page 14 of 184
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[49]. Upon addition of Cys within 30 min, DMF and Cl on 17 are rapidly displaced with 2 mol of thiolates by forming complex 18, with an evident emissive color change from green to orange. After 30 min, complex 19 was formed, with an emissive color change from orange to green, through the intramolecular cyclization reaction to form a six-membered ring via replacement of one of the thiolates
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by the amino group.
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Insert Figures 7-8 Herein
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4.1.1.4. Others
Gold Complexes: Tae et al. reported a rhodamine-based gold complex 20-Au+ (Figure 9) that
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exhibited colorimetric and fluorescent turn-on selectivity and sensitivity toward Cys compared with the other AAs examined through color changes from colorless to red and changes in emission spectra [50].
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Binding of the thiol group of Cys to complex 20-Au+ increases the acidity of the thiol proton. The
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proton released subsequently stabilizes the open form of the rhodamine probe to obtain complex 21.
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Simple thiols, such as propanethiol, cannot induce changes in the fluorescence intensity of 20-Au+. Cerium Complexes: The selective recognition of Trp by metal–organic tetrahedral Ce(22) [51] was reported by Duan and Jia et al. (Figure 10). When Trp was added to Ce(22), the luminescent emission was enhanced, leading to the association between Ce(22) and Trp in 1:1 stoichiometry, with an association constant (logKass) of 3.14±0.27. Given the synergistic effects of hydrogen bonding, πstacking, and size/shape matching, 0 mM to 0.1 mM of Trp can be detected quantitatively. Ce(22) can be used to detect Trp in living systems and serum samples. By contrast, peptides containing Trp residues [52] were not detected range with the use of Ce(22) because of size restriction. Aluminum Complexes: Lodeiro and Oliveira et al. detected a turn-on selective fluorescent probe, aluminum complex of 23 (Figure 10), for His in HEPES buffer and in real urine samples [53]. The 15 Page 15 of 184
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fluorescence intensity of 23 (10 μM) was enhanced 10-fold by His (30 μM). By contrast, the addition of His (30 μM) to the system 23-Al3+ (10 μM) induced a stronger enhancement (100-fold) in the emission intensity. The association constants logKass were (1(23):1Al3+) = 5.63 ± 0.02, (1(23):2His) = 10.4 ± 0.01, and (1(23):1Al3+:2His) = 8.99 ± 0.02.
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Silver Complexes: Kumar and coworkers synthesized the thiacalix[4]arene-based fluorescent receptor 24 (Figure 11), which showed good selective binding ability to Ag+ and Fe3+. Ag+(24) and
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Fe3+(24) (illustrate in section 4.1.2.5.) complexes were then prepared for Cys detection [54]. Compound
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24 produced weak monomer and strong excimer emissions of the pyrene group at 377 and 470 nm, respectively, indicating that the two pyrene moieties on 24 are stacked together. Coordination of 24 with
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Ag+ produced a ratiometric response, in which I377/I470 increased. Quenching in excimer emission was attributed to conformational change via the interaction of Ag+ with nitrogen atoms of pyrene arms and
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sulfur atoms of the thiacalix[4]arene moiety of 24. Addition of Cys to the Ag+(24) complex induced a significant quenching in the monomer emission and a small revival of excimer emission, revealing that
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the Ag+(24)complex.
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the stacking of two pyrene moieties was prevented because Cys is unable to remove the Ag+ ion from
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Cobalt Complexes: Wang et al. constructed an optode membrane by immobilizing the sensing material, 25 (Figure 12), as a fluorescent reporter [55]. 25 consisted of meso-tetraphenylporphyrin cobalt(II), as a molecular probe, and the covalent attachment of meso-tetraphenylporphyrin. The low fluorescence emission of the porphyrin dimer at 657 nm was attributed to photoinduced electron transfer (PET) from the inner free-base porphyrin in the singlet excited state to a low-spin cobalt(II). The fluorescence enhancement of the membrane by His is based on the favorable extraction of His into the bulk organic membrane and the complexation with the inner metallopophyrin moiety as well as the inhibition of PET process. The optode membrane can be prepared easily and is selective to His over several AAs and common anions.
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Insert Figures 9-12 Herein
4.1.2. Using Displacement Approach
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Chemosensing ensemble of metal–organic complexes is one of the most successful strategies for detecting AAs because it provides specific metal ion–AA interactions. In the displacement approach,
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AA competes for the metal ion in the complex of the conjugate during recognition events, thereby
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simply changing the metal ion or ligand of the ensemble.
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triggering a change in optical properties. Such a phenomenon can be used to detect AAs selectively by
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4.1.2.1. Zinc Complexes
In the search for molecular systems that provide selectivity, conjugates of calixarenes are
d
noteworthy because these contain both a hydrophobic cavity and a hydrophilic rim, and can also provide
te
an ideal platform for the development of receptors towards ions or molecular species depending upon
Ac ce p
their functionalization [22c]. Rao and coworkers have been active in developing calix[4]arene conjugates-metal chemosensors, and much impressive progress has been made recently (zinc complexes, silver complexes and cadmium complexes in sections 4.1.2.1, 4.1.2.3 and 4.1.2.5, respectively). Rao and coworkers reported a chemosensing ensemble of calix[4]arene conjugates 26–30 and Zn2+ ions for the selective detection of AAs (Figures 13-15). Among the naturally occurring AAs, Zn(26) (Figure 13) recognizes Asp, Cys, His, and Glu by exhibiting significant fluorescence quenching [56]. The ability of each AA to quench the fluorescence of Zn(26) showed the following trend: Asp > Cys >> Glu ≈ His, which was attributed to the protonation and chelating ability of the AAs as well as the π–π interaction ability of the side chain of the AAs with Zn(26). The fluorescence of Zn(27) (Figure 13) quenched by chelating with Cys and Asp was investigated among the 20 naturally occurring AAs [57]. 17 Page 17 of 184
Edited May 11
The fluorescence quenching observed in the presence of these AAs was attributed to the protonation of the Zn2+ coordination sphere, followed by the formation of a complex of Zn2+ with the AAs. Zn(28) (Figure 14) was utilized to probe Cys, in a fluorescence turn-off manner, which can be attributed to displacement of Zn2+ from Zn(28) by release of free 28 [58]. Zn(29) (Figure 15) could recognize His
ip t
and Cys in HEPES buffer milieu and in HeLa cells. The successful sensing of His and Cys is due to the interaction of His and Cys with Zn2+, followed by the removal of Zn2+ from the coordination sphere
cr
[59]. Compound 30 (Figures 13) exhibited enhanced and blue shifted fluorescence from 535 nm to 495
us
nm upon titration of Zn2+ by forming the Zn(30) complex. Zn(30) showed selectivity toward His, which may be ascribed mainly to the dechelation of Zn2+ from the coordination sphere of Zn(30), followed by
an
formation of the His complex using its side chain imidazole [60].
1,1′-binaphthyl derivatives have been widely used as optical fluorophores due to their special C2
M
axial chirality, rigid structure, relatively high emission efficience and readily selective functionalization [61]. Metal complexes with fluorophores of 1,1′-binaphthyl compounds, such as 1,1′-bi-naphthol
d
(BINOL) etc. have been utilized for the recognition of AAs (zinc complexes of 31 in section 4.1.2.1,
te
copper complexes of 41, 131 and 132 in sections 4.1.2.2, 6.1.1.2 and 6.2, respectively). In 2013, Li,
Ac ce p
Wang, and Yu et al. developed a Zn2+ complex of BINOL derivative 31 for probing His (Figure 13) via a displacement mode [62]. Upon titration of the 31-Zn2+ ensemble with His, the fluorescence intensity decreased, which could be attributed to dechelation of 31-Zn2+ and formation of the His-Zn2+ complex.
Insert Figures 13-15 Herein
4.1.2.2. Copper Complexes
Many AAs show strong binding ability to Cu2+, which indicates its ability as a powerful ligand over others in competitive complexation with Cu2+ [63]. Therefore, the AAs probe can be realized 18 Page 18 of 184
Edited May 11
conceptually using the “chemosensing ensemble” method, i.e. the design of a complex between Cu2+ and an indicator. This probe works simply by releasing the indicator from its copper complex by exchange with a special AA. In addition, the indicator forms a copper complex with a relatively weaker binding constant than the AA [64-65]. Following the “chemosensing ensemble” approach, several recent
ip t
examples have been described according to the signaling fluorophores (indicator). Eosine Y fluorophore: Fabbrizzi et al. described the recognition of His using the [Cu2(32)]4+
cr
complex [66] as a receptor and eosine Y (33) as a fluorescent indicator (Figure 16). [Cu2(32)]4+
us
quenched the fluorescence of 33 by forming a nonfluorescent [Cu2(32)]4+/33 1:1 ensemble with Kass = 107.2 M-1. The [Cu2(32)]4+/33 ensemble showed high selectivity toward His among the other AAs tested,
an
which was attributed to the selective recognition of the ambidentate imidazole residue of His over the carboxylate group of natural AAs. His could displace the indicator of 33 from the receptor of
M
[Cu2(32)]4+. 33 was released from the ensemble and the fluorescence was revived. Near-infrared (NIR) fluorophore: Zwitterionic dye 34 (Figure 17) showed NIR fluorescence
d
emission [6]. After adding Cu2+ to the DMF solution of 34, the emission of 34 was quenched and a
te
hypsochromic shifted from 875 to 850 was observed along with an immediate color change from blue to
Ac ce p
yellow. This was attributed to metal-to-ligand charge transfer (MLCT). The stoichiometry of the 34-Cu complex was confirmed to be 2 : 1 with a binding constant of 4.44×108 M-2. Upon exposure to Cys from 0 to 20 × 10-5 M, the blue-colored and NIR fluorescent 34 was released from its non-fluorescent copper complex (34-Cu), with a high-contrast colorimetric change from yellow to blue. 34-Cu could discriminate Cys selectively among the other analogs due to the cooperative effect of the thiol-aminocarboxylic acid moiety in Cys as a ligand to Cu2+ and the larger binding constant of Cys/Cu2+ (5.91×108 M-2) than that of 34/Cu2+ (4.44×108 M-2) and those of the other AAs with Cu2+. Dansyl fluorophore: Wu et al. developed a dual-functional probe for Cys and His based on the ensemble of 35 and Cu2+ (Figures 18) [67]. 35 responded to Cu2+ with fluorescence quenching and a binding constant of 3.98 × 106 M-1 in 1:1 stoichiometry. The fluorescence emission of 35 could be 19 Page 19 of 184
Edited May 11
released from complex Cu2+(35) upon the addition of His or Cys through different sensing process. The fluorescence recovery induced by His was attributed to the displacement mechanism, where His could capture Cu2+ from the Cu2+(35) complex, whereas the other AAs were faint because the stronger binding affinity between 35 and Cu2+ exceeded the binding between Cu2+ and most of the other AAs. The turn-
ip t
on detection of Cys was attributed to the reduction of a thiol group in Cys, which reduced the paramagnetic Cu2+ to diamagenetic Cu+. Therefore, the fluorescence of 35 quenched by Cu2+ was
cr
recovered.
us
Rhodamine fluorophore: Upon mixing with Cu2+ ions, the 36-Cu2+ complex (Figure 19) [68] was formed with a pink color and weak fluorescence, which might be due to the paramagnetic nature of Cu2+
an
ions (3 d9), and the fluorescence of the ring-opened amide form of 36 was quenched. When rhodamine B was introduced to a 36-Cu2+ complex solution, the fluorescence signal of rhodamine B was reduced
M
dramatically due to the overlap between emission spectra of rhodamine B and absorption spectra of 36Cu2+ through the fluorescence inner filter effect (IFE). The addition of Cys to the above solution
d
resulted in the preferential formation of a complex with Cu2+ compared with 36, resulting in the
te
dissociation of the 36-Cu2+ complex and a decrease in the fluorescence IFE of the solution. The
Ac ce p
fluorescence emission of rhodamine B was then measured. The displacement of the Cu2+ ion in the 36Cu2+ complex is not an exclusive feature of Cys, the present system can also show a similar response to other thiol-containing compounds, such as Hcy and GSH.68 Coumarin fluorophore: Yu and Li et al. used a Cu2+ complex of coumarin-based ligand 37 (Figure 20) as a selective turn-on fluorescent sensor for His from other naturally occurring AAs in aqueous solution and in biological fluids, such as human urine and fetal calf serum [69]. Compound 37 formed a nonfluorescent complex with Cu2+ in 1:1 binding mode, and the binding constant was 1.3×106 M−1. His was used to remove Cu2+ from the 37-Cu2+ complex because His with Cu2+ has a larger formation constant (log β1=10.16 and log β2=18.11) than that of 37 and Cu2+. The use of His resulted in ~80-fold enhancement of fluorescence at 500 nm upon addition of 120 equiv. relative to Cu2+. 20 Page 20 of 184
Edited May 11
Recently, Chan and Leung et al. also developed a coumarin-based ligand 38-Cu2+ complex (Figure 20) for the selective detection of His in a turn-on manner, which is applicable not only to aqueous solutions but also to living cells [70]. Upon adding His into the 38-Cu2+ ensemble, His is capable of removing Cu2+ from its ensemble by cooperative chelating action of the carboxyl and imidazole
ip t
moieties of His. The binding model of His-Cu2+ was 2:1, with an association constant of 2.54×109 M−2. Meanwhile, fluorescence recovery was also achieved by titrating the 38-Cu2+ ensemble with biothiols,
cr
Cys, Hcy, and GSH.
us
BODIPY fluorophore: Shao et al. prepared an ensemble of BODIPY-based derivative 39 and Cu2+, which was then used as a chemosensor for Cys and Hcy (Figure 21) [71]. Only Cys and Hcy induced
an
enhancement in fluorescence among the 20 natural AAs and Hcy because of the removal of Cu2+ from the 39·Cu2+ complex, resulting in fluorescence recovery of 39.
M
Quinazoline fluorophore: The quinazoline derivative 40-Cu2+ ensemble probe (Figures 21) was prepared by Chellappa et al. for the detection of Cys [72]. The addition of Cys induced decomplexation
d
of Cu2+ from the weakly fluorescent ensemble, resulting in restoration of the emission property of 40.
te
BINOL fluorophore: Feng et al. developed a BINOL (41)-based fluorescent thiol sensor (Figures
Ac ce p
22) [73]. Compound 41 showed an emission spectral band at 360 nm. This band was decreased upon the addition of Cu(NO3)2 and completely quenched with 1.0 equiv. Cu(NO3)2. In this process, 41 was oxidized to 42 and Cu(42) was formed. When Cys, Hcy, or GSH was added to Cu(42), the chelation of thiol-containing AAs with copper occurred, instead of the formation of Cu(42), thereby inducing fluorescence enhancement at 482 nm and green fluorescence under UV light, which corresponded with the fluorescence of 42. Recognition ability was in the following order: Cys/GSH > Hcy. Naphthalimide fluorophore: The ensemble of Cu2+ and naphthalimide-based ligand 43 (Figures 23) was designed as selective fluorescent thiol probe [74]. The fluorescence of the 43-Cu2+ ensemble was enhanced by thiols because of the replacement of Cu2+ from the ensemble by thiols and the release of fluorescent ligand 43. From the titration experiments, the association constants (logKass) were 4.02 for 21 Page 21 of 184
Edited May 11
Cys, 3.88 for Hcy, and 3.68 for GSH. In addition, the 43-Cu2+ ensemble showed high sensitivity and selectivity for fluorescence imaging of thiols in Chinese hamster ovary cells. Calix[4]arene derivative: The fluorescence of 30 (Figure 13) was completely quenched in the presence of Cu2+ [60]. 30-Cu2+ complex showed increased fluorescence intensity in the presence of Cys
ip t
among all the 20 AAs investigated, indicating the interaction of Cys with Cu2(30), followed by the
cr
dechelation of Cu2+ from the coordination sphere of this complex to form the Cys·Cu adduct.
us
Insert Figures 16-23 Herein
an
4.1.2.3. Silver Complexes
M
Rao et al. reported that the fluorescent receptors 44 and 45 for Ag+ can be used as a secondary recognition ensemble toward AAs. Calix[4]arene derivative 44 (Figure 24) [75] and Ag+ formed a 1:1
d
complex with an association constant (Ka) of 11117 ± 190 M-1. During the titration of 44-Ag+ with Cys,
te
Ag+ is being removed from the complex by Cys to release free 44 and the necessity of the -SH function
Ac ce p
on Cys was confirmed after removing the Ag+ from 44-Ag+ complex based on several analogous and control molecules. The 45-Ag+ ensemble (Figure 24) realized recognition toward Cys, Asp and Glu against 20 naturally occurring AAs [76], by switching-off the fluorescence of 45-Ag+. This was the reverse to what occurred when 45 was titrated with Ag+, indicating the removal of Ag+ by Cys and the release of free 45.
Insert Figure 24 Herein
4.1.2.4. Mercury Complexes 4.1.2.4.1. Chemosensing of Cys 22 Page 22 of 184
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In view of the strong affinity of Hg2+ towards thiols, the utility of the Hg2+ complexes for the detection of thiol based AAs, such as Cys, have receive highly interest from researchers. Wang et al. and Fu et al. proposed squarine-Hg2+ ensemble fluorescence assay for thiol containing AAs (Figure 25).
ip t
After binding with Hg2+, the fluorescence of 46 [77] and 47 [78] gradually extinguished due to the diminishment of the electron-donating ability of nitrogen atom that destroyed the donor–acceptor–
cr
donor (D–A–D) charge transfer upon the chelation of Hg2+ into the terminal binding units of 46 and 47.
us
Upon addition of thiol-containing AAs, the complex of 46-Hg2+ or 47-Hg2+ was dissociated, releasing free 46 or 47 from the ensemble owing to the stronger binding between thiols and Hg2+.
an
Correspondingly, 46-Hg2+ or 47-Hg2+ exhibited emission enhancement. The tunable measuring ranges of Cys can be achieved by varying the Hg2+ concentrations in the 47-Hg2+ ensemble.
M
Mahapatra et al. also used the ensemble strategy in designing a combination of carbazole derivative 48 (Figure 26) and Hg2+ to fabricate a turn-on fluorescent Cys probe [79]. Upon the addition of Hg2+, a
d
complex of 48-Hg2+ was formed, inducing a decrease in fluorescence as well as the solution color
te
change from nearly colorless to yellow. On increasing the concentration of Cys, the 48-Hg2+ complex
Ac ce p
decomposed to release 48 and the emission recovered. Compared with Cys, other mercapto biomolecules, such as Hcy and GSH, induced relatively slight increases in fluorescence. Singh et al. reported an Hg2+ complex of the crown ether–BODIPY ligand 49 that operates as an on–off fluorescence sensor for L-Cys over other AAs [80]. As shown in Figure 27, the recognition of Cys could be attributed to the release of 49 from the 49-Hg2+ complex (binding constant logβ=4.55), and the formation of the Cys-Hg2+ complex (binding constant logβ=6.33) resulted from the removal of Hg2+ by Cys. In addition, the Hg2+-doped hydrogel in the presence of 49 can be applied qualitatively to Cys sensing via gel–sol conversion and color changes from light orange to pink. Chellappa et al. developed an off–on fluorescent sensor based on the ensemble of quinazoline derivative 50 and Hg2+ (Figure 28) [81] that can be used to detect Cys. Addition of Cys caused 23 Page 23 of 184
Edited May 11
fluorescence restoration of 50, indicating the removal of Hg2+ from the ensemble. Jiang et al. and Lin et al. used an aggregation and deaggregation strategy in the design of perylene bisimide (PBI) derivatives 51 [82] and 52 [83] for detecting thiol-containing AAs (Figure 29). The fluorescence of 51 and 52 was quenched completely after adding Hg2+ by forming the nonfluorescent H-
ip t
aggregated Hg2+-51 ensemble and J-aggregated Hg2+-52 ensemble, respectively, via the thymine–Hg2+– thymine (T-Hg2+-T) binding mode. The quenched fluorescence of the Hg2+-51/52 ensemble was
cr
recovered upon the addition of thiol-containing AAs via deaggregation of the Hg2+-51/52 ensemble to
us
restore the PBI state 51/52.
Luo and Li et al. observed the response of the reduced graphene oxide (rGO)–organic dye 53-Hg2+
an
ensemble toward Cys (Figure 30) [84]. The fluorescence of 53 was quenched after titrating with rGO to form the rGO–53 complex because of long-range resonance energy transfer. In the presence of Hg2+,
M
highly selective adsorption of Hg2+ by rGO disrupted the interaction between 53 and rGO, thus restoring the fluorescence of 53. Upon adding Cys to the ensemble of rGO–53-Hg2+, Hg2+ was released from
d
rGO, which is attributed to the stronger binding of Hg2+ and Cys, resulting in reformation of the rGO–
Ac ce p
te
53 complex and fluorescence requenching of 53.
4.1.2.4.2. Chemosensing of other AAs
Very recently, a chemosensing ensemble of 54-Hg2+ toward L-pro was examined by Pal and Bag (Figure 31) [85]. The complex of 54-Hg2+ presented high selectivity toward L-pro among different AAs investigated in an absorption or fluorescence turn-off manner; a color change from pink to colorless was also observed. In 2012, our group designed a highly ordered mesoporous SBA-15 nanosensors 55 (Figure 31) that is capable of binding Hg2+ and detecting 20 natural α-AAs except for Trp, by a Hg2+-mediated approach [86]. After binding Hg2+, the fluorescence emission of 55 quenched due to the PET process from the 24 Page 24 of 184
Edited May 11
exited dansyl moiety to the proximate Hg2+, with Kass of 1.32 × 105 M-1 between 55 and Hg2+. The successful sensing of α-AAs has been realized by snatching Hg2+ from the 55–Hg2+ due to the larger stability constant of the complex formed by the α-AAs and Hg2+ compared with that of 55 and Hg2+, in
ip t
which the quenched fluorescence of 55 by Hg2+ was recovered.
cr
Insert Figure 25-31 Herein
us
4.1.2.5. Others
an
Cadmium Complexes: Rao et al. used the combination of the calix[4]arene derivative 56 and Cd2+ (Figure 32) [87] to fabricate an on–off fluorescence Cys probe, with a visual color change from blue to
M
dark. When Cys concentration was increased, the fluorescence intensity initially increased to a small extent, and then decreased gradually until it attained saturation, suggesting the involvement of –SH on
d
Cys in the binding of Cd2+, followed by its removal from the complex. Cellular studies using MCF-7
te
cells showed that this system can be utilized for in vivo imaging of Cd2+ and Cys.
Ac ce p
Aluminum Complexes: Xin and coworkers developed an Al3+ complex sensor based on bisrhodamine B thiourea conjugate 57 for Arg detection (Figure 33) [88]. Addition of Al3+ induced fluorescence enhancement, with the solution changing from colorless to pink through formation of the 1:1 57-Al3+ complex, with a binding constant (logKass) of 4.4. Among the AAs tested, only Arg completely quenched fluorescence, with the solution changing from pink to colorless, whereas the other AAs caused only a slight change on the emission and color of the 57-Al3+ complex. The 57-Al3+ complex exhibited a linear fluorescence on–off response to Arg that could be monitored up to 1.2×10−4 M. The off–on–off response of 57 to Al3+ and Arg is due to the stronger interaction of Arg with Lewis acidic Al3+, leading to the structural transformation of rhodamine B on 57 in the process of spiro ring structural formation (nonfluorescent)–ring opening (57-Al3+, strong fluorescence)–spiro ring structural formation (57-Al3+ + Arg). 25 Page 25 of 184
Edited May 11
Iron (Fe3+) Complexes: Addition of Fe3+ caused significant quenching in the monomer and excimer emission of 24 (Figure 11) [54], which was attributed to the PET process from pyrene units to carbonyl oxygen and the conformational changes of two pyrene-appended arms, respectively. The Fe3+(24) complex exhibited a significant increase in monomer and excimer emission intensities when Cys was
ip t
added. Complete revival of fluorescence emission is due to the complete removal of Fe3+ from the Fe3+(24) complex by Cys.
cr
Others: The chemosensing ensemble of 30-Zn2+ (section 4.1.2.1.) and 30-Cu2+ (section 4.1.2.2.)
us
underwent an on–off His sensing and an off–on Cys sensing, respectively [60], because of the dechelation of metal ions to form an His/Cys complex of metal ions. Rao and coworkers also utilized
an
the same strategy in the design of the Mn2+, Fe2+, Co2+, and Ni2+ complexes of 30, namely, [Mn230], [Fe230], [Co230], and [Ni230], which can be applied to AA sensing in a turn-on manner [60]. Among the
M
20 AAs investigated, [Co230] induced fluorescence enhancement of three AAs to different extents in the following order: His > Asp > Cys, with minimum detection concentrations {in ppm (µM)} of 0.53
d
(3.44), 0.34 (2.5), and 0.68 (5.65), respectively. [Mn230] signaled the recognition of Asp and Glu, with
te
minimum concentrations of 2.8 ppm (19.0 µM) for Glu and 2.67 ppm (20.2 µM) for Asp. [Ni230]
Ac ce p
exhibited high selectivity toward His over two AAs in the following order: His > Asp > Cys. [Fe230] showed no response to the AAs.
Insert Figure 32-33 Herein
4.1.3. Using Chemodosimeter Approach 4.1.3.1. Platinum Complexes
Lam et al. developed heterobimetallic chemodosimetric ensembles, 58, 59 and 60 (Figure 34) that could distinguish certain sulfhydryl-containing AAs/peptides [89], such as Cys, Hcy, Met and GSH, in 26 Page 26 of 184
Edited May 11
which the Pt(II) metal center acted as a functional-specific binding site that was bridged to the Mdiimine chromophore (M=Fe2+, Ru2+, Os2+) via cyano bridges. Upon an interaction with Cys, Hcy, Met and GSH, the luminescence of 58, 59 or 60 was increased and red-shifted due to the binding of the thiolcontaining AAs to the Pt(II) centers, and the subsequent cleavage of the cyano bridge and restoration of
ip t
the characteristic 3MLCT luminescence of Fe2+/Ru2+/Os2+-diimine chromophore. Complex 61 (Figure 35) [90] exhibited improved selectivity for Cys among 20 natural AAs investigated. The luminescence
cr
of 61 was quenched after interacting with Cys due to chloride displacement and the formation of the Pt-
us
S(Cys) bond. The lack of a response of 61 for Met was attributed to the hindered lone pair and lower nucleophilicity for the -SMe unit than the -SH group.
an
Phen has several appealing structural and chemical properties: rigidity, planarity, aromaticity, basicity and chelating capability. This makes it a versatile starting material for synthetic organic,
M
inorganic and supramolecular chemistry [91]. Phen, a weakly fluorescent molecule, has been used in the
such as Pt, Ru, Ir, etc.
d
design of many UV-Vis-NIR luminescent organic derivatives and coordination compounds with metals,
te
By incorporating Phen, the platinum(II) complexes of 62 (Figure 36) and 63 exhibited intense
Ac ce p
orange emission and green luminescence, respectively [92]. After adding Cys/Hcy, the emission of 63 was quenched and red-shifted from 510 to 555 with a luminescence color change from green to orange, due to the formation of a thiazinane group through a selective reaction of the aldehyde group of 63 with Cys/Hcy. The important role of the aldehyde group on 63 in interacting with Cys was confirmed by investigating the contrast complex of 62. Other AAs induced no obvious luminescence changes in 63 and the detection of Hcy/Cys was unaffected by the presence of 100 equiv. of other AAs or GSH.
Insert Figures 34-36 Herein
4.1.3.2. Iridium Complexes 27 Page 27 of 184
Edited May 11
These iridium complexes that applied in detecting AAs, were formed through coordinating two kinds of organic ligands with the iridium center. The reported examples are listed according to the ligands.
ip t
Using 4-(2-pyridyl)benzaldehyde (pba) as a co-ligand: Lo et al. reported a series of luminescent cyclometalated iridium(III) complexes (Figure 37) containing two aldehyde functional groups,
cr
[Ir(pba)2(N-N)](PF6) (N-N=2,2’-bipyridine, bpy (64), phen (65), 3,4,7,8-tetramethyl-phen (66), 4,7-
us
diphenyl-phen (67)) [93], which can conjugate with Ala. In their study, they did not examine the sensitivity and selectivity of the iridium(III) complexes 64-67 toward AAs. Therefore, the only
an
information could be obtained was that 64-67 were conjugated with Ala and induced changes in the emission spectra.
M
Li et al. reported a highly selective luminescent chemosensor (Figure 38), Ir(pba)2(acac) (68, acac=acetylacetone) [94] for Hcy over other AAs (including Cys) and thiol-related peptides (including
d
GSH). After titrating with Hcy, the emission band was blue-shifted, and the luminescence intensity was
te
increased due to a reaction of the aldehyde moiety with Hcy to form thiazolidines with an emission
Ac ce p
color change from deep red to green, which could be observed by the naked eye. Probes 69 (with pba and bpy liangds, Figure 38) [95] and 70 (with pba and phen-derived liangds, Figure 39) [96] and mesoporous silica-based nanoprobe 71 (with pba and 3-hydroxypicolinic acidderived liangds, Figure 40) [97] were used by Zhao, Huang, and coworkers as selective luminescent probes for Cys and Hcy over other AAs. The recognition mechanism involves the reaction of the aldehyde group in 69, 70, or 71 with the β-aminoalkylthiol and γ-aminoalkylthiol groups of Cys and Hcy to form the corresponding thiazolidine/thiazinane derivatives. Using 2-phenylpyridine and Phen/bpy-derived ligands: Che et al. reported that fluorescence resonance energy transfer (FRET)-based iridium complex 72 (Figure 41) [98] exhibits high selectivity for Hcy and Cys over the other 19 AAs and GSH. The luminescent emission of 72 (25 µM) was 28 Page 28 of 184
Edited May 11
increased up to 88-fold and 65-fold in the presence of Hcy (0 mM to 2.5 mM) and Cys (0 mM to 2.5 mM), respectively, because of the cleavage of the vinyl sulfide linkage of 72 by the nucleophilic Hcy or Cys (the vinyl sulfide linkage can only be cleaved by thiols, not by other nucleophiles, such as amines and alcohols [99]). The difference in emission intensity enhancement in the detection of Hcy and Cys by
ip t
probe 72 is attributed to a lesser bulky thiol group on Hcy than on Cys. Moreover, the iridium probe 73 with a tert-butyl group could differentiate Hcy from Cys at a ratio of 5:1 [98].
and
quantifying
Hcy+Cys
and
Trp
through
the
photoluminescence
(PL)
and
us
detecting
cr
As shown in Figure 42, Schmittel and Chen described the use of iridium complex 74 [100] for
electrochemiluminescence (ECL) channels, respectively. Complex 74 exhibited PL enhancement in the
an
presence of Hcy and Cys because of the aldehyde cyclization reaction. ECL quenching was observed at 602 nm in the presence of Trp because of its electroactivity.
M
The cyclometallated iridium complex 75 (Figure 43) [101], containing an α,β-unsaturated ketone moiety as a conjugated spacer, was used as a probe for the selective detection of thiols. For the 20
d
naturally occurring AAs, complex 75 showed specific selectivity toward thiols. For instance, the
te
luminescence intensity of 75 (20 mM) was enhanced 20-fold upon the addition of 80 equiv. of Cys
Ac ce p
because of the formation of a thioether in the adduct 76 by 1,4-addition of Cys to the α,β-unsaturated ketone of 75. The reactivity of the thiols to complex 75 showed the following trend: Cys > Hcy > GSH, which is consistent with the order of the steric hindrance effect. Using other ligands: Zhao, Li, Huang, and coworkers developed an ET-based iridium probe 77 (Figure 44) that can detect Cys and Hcy [102]. Probe 77 is non-emissive because of the ET process from the Ir3+ center and ligand 79 to the strong electron acceptor 2,4-dinitrobenzenesulfonyl (DNBS). Upon the addition of Cys and Hcy to probe 77, the luminescence of 78 is switched on because of the cleavage of the sulfonate ester of probe 77 by Cys and Hcy to form complex 78. Chao et al. developed a non-emissive dinuclear iridium complex 80 (Figure 45) [31] for the selective detection of thiols with mercapto groups, including Cys, Hcy, and GSH, under weakly acidic, 29 Page 29 of 184
Edited May 11
neutral, and weakly basic conditions, as well as imaging thiol levels in living cells. The phosphorescence intensity of 80 (5.0 μM) was enhanced 30-fold, 38-fold, and 35-fold upon the addition of Cys (50 μM), Hcy (50 μM), and GSH (50 μM), respectively, through the redox reaction between the
ip t
thiol and azo groups of 80.
cr
Insert Figures 37-45 Herein
us
4.1.3.3. Ruthenium Complexes
an
As luminescent probes, Ru(II) complexes have several desirable features including the intense visible absorption and emission, large Stokes shift, high photo-, thermal and chemical stability and very
M
low cytotoxicity [103-104]. Owing to these outstanding photochemical and photophysical properties, sensitive and selective luminescence probes based on Ru(II) complexes, particularly the Ru(II)-phen
d
complexes and Ru(II)-bpy complexes, have been developed for the recognition and detection of thiol-
te
containing AAs, such as Cys and Hcy, etc.
Ac ce p
Ru(II)-phen complexes: Lam et al. developed a heterobimetallic chemodosimetric ensemble, cisRu(phen)2-[CN-Pt(DMSO)Cl2]2
(81) (Figure 46) [105], that could be selective for sulfhydryl-
containing AAs and peptides, in which the Pt(II) metal center acted as a functional-specific binding site and was bridged to the indicator of the Ru(II)-diimine chromophore responsible for signal transduction. Complex 81 weakly emitted due to the coordination of two Pt(DMSO)Cl2 moieties to a Ru(II) center via cyano bridges. Upon an interaction with Cys, Hcys, Met and GSH, the luminescence of 81 was increased and red-shifted due to the binding of the thiol-containing AAs to the Pt(II) centers of 81, and the subsequent cleavage of the cyano bridge and restoration of the characteristic orange-red 3MLCT luminescence of Ru(II)-diimine chromophore. Zhao et al. used phosphorescent probe 82 (Figure 47) with an off–on switch effect for selective 30 Page 30 of 184
Edited May 11
detection of thiols [106]. Probe 82 is nonluminescent because of the efficient PET between the potent electron donor (Ru center) and strong electron acceptor (DNBS). The phosphorescence of 83 was switched on because the typical MLCT photophysics of the Ru2+ complex 83 with the N∧N ligand as electron acceptor was reestablished by cleavage of DNBS on 82 with thiols.
ip t
Ru(II)-bpy complexes: Yuan and Zhang et al. designed a DNBS-protected bpy-Ru2+ complex 84 probe for PL and ECL detections of Cys and GSH (Figure 48) [107]. Complex 84 emits weak MLCT-
cr
based PL because of the intramolecular PET process from the Ru2+ center to the electron acceptor
us
DNBS. Fluorescence turn-on in the presence of Cys and GSH is due to cleavage of DNBS by thiols, leading to recovery of MLCT-based luminescence of the complex 85. The probe was then applied to
an
detect biothiols in HeLa cells. Similarly, ECL enhancements were observed upon the addition of Cys and GSH. The FL and ECL intensities showed good linear relationships with the concentrations of Cys
M
and GSH, ranging from 0 µM to 10 µM for Cys and GSH. Through ECL titration, the LODs are 86.5 nM and 56.3 nM for Cys and GSH, respectively.
d
The cyclization reactions of Cys and Hcy with organic aldehydes on Ru2+ complexes have been used
te
to detect Cys and Hcy by forming thiazolidine and thiazinane derivatives. 86 with three aldehyde
Ac ce p
substituted bipyridine ligands (Figure 49), was designed for the selective recognition and sensitive detection of Cys/Hcy [108]. 86 was almost nonluminescent because the strong electron-withdrawing aldehyde group in the ligand can effectively quench the MLCT luminescence of the Ru2+ complex. 86 can react rapidly and specifically with Cys/Hcy to form the corresponding thiazolidine and thiazinane derivatives, resulting in a remarkable enhancement of MLCT emission and a large blue-shift in the maximum emission wavelength from 720 nm to 635 nm due to the disappearance of the electronwithdrawing effects of the aldehyde group. The ruthenium complexes 87-90 (Figure 50) [109] exhibited selective recognition of Hcy and Cys. For example, the emission intensity of 90 (7.0 μM) was enhanced 10.1-fold and 4.5-fold upon the addition of Hcy (0.7 mM) and Cys (0.7 mM), respectively. The formation of thiazinane and thiazolidine 31 Page 31 of 184
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played a key role in the selective recognition of Hcy and Cys, whereas little or no increase in luminescence was observed upon the addition of other AAs. All the complexes 87-90 were more sensitive to Hcy than Cys, probably because of the easier formation of thiazinane. Substitution with an electron-donating group (CH3) on bipyridine would also improve the recognition ability of the
ip t
complexes for Hcy and Cys. Chao, Ji, and coworkers reported that dinuclear Ru2+ complex 91 (Figure 51) can be used to probe
cr
thiols, such as Cys, Hcy, and GSH, over the other 19 natural AAs [110]. Complex 91 showed weak
us
luminescence because of the PET process. Upon exposure of 91 (10 μM) to Cys (0.2 mM), Hcy (0.2 mM), and GSH (0.2 mM), the luminescence intensity was enhanced by 35-fold, 36-fold, and 33-fold,
an
respectively, with the original gray color of 91 turning yellow because of the inhibition of the PET
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process through reduction of the azo group into the azo2− form by these thiols.
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Ac ce p
4.1.3.4. Copper Complexes
d
Insert Figure 46-51 Herein
Kang and Kim et al. reported the first copper complex, iminocoumarin-Cu2+ ensemble (92-Cu2+) (Figure 52) [111], used for thiol detection based on a chemodosimetric method. Owing to the thiol specific affinity of a copper ion, an off–on fluorescence change in 92-Cu2+ was observed by the addition of thiols (GSH, Hcy and Cys), which induced decomplexation of the Cu2+ ion from non-fluorescent 92, followed by the hydrolytic cleavage of 92 to yield a strongly fluorescent coumarinaldehyde 93 in aqueous solutions. Competitive experiments confirmed that the selective response of 92-Cu2+ to thiols was unaffected by the presence of other AAs. Chen et al. devised an iminofluorescein-Cu2+ ensemble probe 94-Cu2+ (Figure 53) for detecting Cys [112]. Fluorescent probe 94 exhibits a fluorescence quenching effect with Cu2+. The addition of 32 Page 32 of 184
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Cys induces the off–on-type fluorescence enhancement, which was ascribed to the decomplexation of the 94-Cu2+ ensemble, followed by hydrolysis of the Schiff base to form a strongly fluorescent fluoresceinaldehyde 95. The ensemble exhibited a similar response to other thiol-containing compounds, such as Hcy and GSH. Studies of biological applications showed that this system can be
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utilized for the imaging of thiols in living cells.
us
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Insert Figures 52-53 Herein
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4.2. Polymer-Metal Complexes
Compared with small organic-metal complexes, polymer-metal based systems have the capability to
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improve the sensing performance. For example, polymer chains with multiple recognition elements can increase both the binding effieiency and recognition selectivity for specific AAs and polymer chains
te
d
with multiple signaling elements can enhance the sensitivity.
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4.2.1. Using Displacement Approach 4.2.1.1. Copper Complexes
4.2.1.1.1. Introducing Cu2+ binding sites into the polymer side chains
Li et al. developed imidazole-functionalized polyacetylenes 96 (Figure 54) [113] and 97 (Figure 54) [114] by introducing different functional moieties to the acetylene backbone as side groups to detect αAAs based on a turn-on model via an indirect approach. They also reported conjugated polymer-based fluorescent polyfluorene 98 (Figure 54) [115], which was applied as a chemosensor for indirectly detecting α-AAs. Cu2+ quenched the strong blue fluorescence of 96, 97, and 98 because of the affinity of imidazole moieties to Cu2+. Quenched fluorescence of 96, 97, or 98 was recovered by adding α-AAs to 33 Page 33 of 184
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the 96/Cu2+, 97/Cu2+, and 98/Cu2+ complexes, respectively; Cu2+ was captured from the complexes because of the formation of a stable 2:1 AA/Cu2+ complex [116]. 96/Cu2+, 97/Cu2+, and 98/Cu2+ complexes exhibited high sensitivity to His because of the affinity of imidazole moieties to Cu2+ ions. Fluorescence recoveries for 96, 97, and 98 were 88%, 92%, and 96%, respectively, which suggests that
ip t
96/Cu2+, 97/Cu2+, and 98/Cu2+ complexes could selectively probe His to some degree. Moreover, His can be differentiated from other α-AAs visually by observing the strong blue fluorescence using a
cr
normal UV lamp. Overall, although the selectivity of this system was relatively low, the β-, γ-AAs can
us
also induce the fluorescence recovery of 96, 97, or 98 to some degree, and the influence of β-AAs cannot be omitted. Importantly, this work might open up a new avenue to the development of new
an
biosensors. Fang et al. used the same strategy to design quinolinol-containing conjugated polymer 99 (Figure 54) [117], with side chains functionalized by imidazole, to sense AAs.
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Gao et al. reported that Cu2+ complexes of conjugated polymer 100 can probe Cys, whereas Ni2+ complexes can probe His and Trp (Figure 55) [118]. Cu2+ or Ni2+ can bind with 100 to form 100-Cu2+
d
or 100-Ni2+ complexes, which consequently quenches the fluorescence of 100 because of the energy
te
from conjugated polymer backbone to Cu2+ or Ni2+ ions (i.e., PET process); the calculated Stern–
Ac ce p
Volmer constant Ksv is 4.6×106 M−1 for Cu2+ and 2.19×105 M−1 for Ni2+. Upon adding Cys to 100-Cu2+ complexes or His/Trp to 100-Ni2+ complexes, fluorescence of 100 was recovered by dissociating 100metal complexes and generating favorable and strong (Cys·Ni2+) or (Try·Ni2+) and (His·Ni2+) complexes.
Jayakannan’s group reported two water-soluble carboxylic functionalized distilbene chromophore bearing polymers 101 and 102 [119], which were utilized to sense AAs based on a turn-on model (Figure 56). Cu2+ traces efficiently quenched the strong blue fluorescence of 101 or 102. Six different AAs (i.e., Ala, Ser, Cys, Gln, His, and Trp) were added to 101-Cu2+ or 102-Cu2+ complexes, and quenched fluorescence of 101 or 102 was turned on. Although all six AAs could be detected sensitively, sensing activity depends on the nature of the AA side chain; the order of fluorescence enhancement is 34 Page 34 of 184
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His > Trp and Gln > Ala, Cys, Ser. His recovered high fluorescence intensity because the heterocyclic ring in His bound more strongly to Cu2+ compared with other AAs, while Cys attained saturation level quickly because of the thiophilic nature of Cys to Cu2+. Only 25% of fluorescence was recovered in this system because Cu2+-AA complexes formed incompletely and the thio-group in Cys strongly interfered
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with His selectivity. Su et al. designed Cu2+ complex of water-soluble fluorescent conjugated polymer 103 as a turn-on
cr
fluorescent probe for Cys and GSH (Figure 56) [120]. Cu2+ quenched the fluorescence of 103 because
us
of the strong electrostatic interaction and ET between 103 and Cu2+. Upon adding Cys or GSH to 103Cu2+, the fluorescence of 103 was recovered because of the thiol functionality in Cys or GSH, which
an
can capture Cu2+ from 103-Cu2+ by forming Cu2+–S bonds.
Pitchumani and Azath constructed a flavone-modified β-cyclodextrin 104 that can selectively
M
detect His (Figure 57) [121]. Cu2+ ions induced strong fluorescence quenching of 104 because of the formation of a non-fluorescent Cu2+-104 complex. Upon adding D/L-His into the Cu2+-104 complex,
d
fluorescence intensity switched on because of the combination of D/L-His and Cu2+ and the release of
Ac ce p
te
104. Cu2+-flavone did not respond to His, which indicates that cyclodextrin cavity is key to sensing His.
Insert Figures 54-57 Herein
4.2.1.1.2. Using the ensembling strategy of DNA and Cu2+
DNA oligonucleotides, which are useful, functional, and structural elements, have recently been proposed to construct sensitive detection platforms for AAs. For example, Ren and co-workers developed single-stranded DNA-1/thiazole orange (105)/Cu2+ and DNA-1/105/Hg2+-based ensemble systems to detect His and Cys, respectively (Figure 58) [122]. 105 was non-fluorescent but exhibited intense fluorescence upon interaction with nucleic acids regardless of base composition. Fluorescence of 35 Page 35 of 184
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105/DNA-1 was quenched in the presence of Cu2+ (or Hg2+). Cu2+ (or Hg2+)-quenched fluorescence of 105/DNA-1 was then restored in the presence of His (or Cys) because of the formation of a stable complex between Cu2+ and His or Hg2+ and Cys. Most AAs do not interfere with fluorescence enhancement induced by His or Cys.
ip t
Ma and co-workers developed a DNA-2/iridium complex 106/Cu2+-based ensemble system (Figure 59) [123] for turn-on detection of His. Wang, Liu, and co-workers applied a similar approach to detect
cr
His using DNA-3/Cu2+/N-methylmesoporphyrin 107 ensemble (Figure 60) [124]. Emission of 106 or
us
107 was significantly enhanced in the presence of G-quadruplex, which implies selective interaction between 106 or 107 and G-quadruplex structure. Adding Cu2+ ions results in conversion of G-
an
quadruplex motif into single-stranded DNA (ssDNA) and diminished system emission. Among the 20 natural AAs, Hcy, and GSH, system luminescence was only restored upon adding His into ensembles
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with N-ethylmaleimide (NEM) as a masking agent for Cys, Hcy, and GSH, because the sequestration of
te
Ac ce p
Insert Figures 58-60 Herein
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Cu2+ preserves the G-quadruplex structure by forming a stable His-Cu2+ complex.
4.2.1.2. Mercury Complexes
4.2.1.2.1. Using the ensembling strategy of DNA and Hg2+
Ye et al. reported a new system for turn-on detection of biothiols with high sensitivity and selectivity based on a Tb3+/DNA-4/Hg2+ ensemble (Figure 61) [125]. Initially, guanine (G)/thymine (T)rich DNA-4 oligos ([G3T]5) sensitized Tb3+ luminescence via efficient intermolecular energy transfer from [G3T]5 ligand to Tb3+. Tb3+/[G3T]5 luminescence was then quenched by Hg2+ because of the interaction between [G3T]5 with Hg2+, which weakened the sensitizing responses of Tb3+ luminescence by [G3T]5. Luminescence gradually increased upon adding Cys in increasing concentrations to the 36 Page 36 of 184
Edited May 11
Tb3+/[G3T]5/Hg2+ ensemble. Turn-on luminescence response was due to the recovery of Tb3+/[G3T]5 luminescence by capturing Hg2+ via the formation of Hg2+-S bond. This ensemble had higher selectivity for biothiols (Cys, Hcy, and GSH) than the other 19 natural AAs and GSH disulfide (GSSG). An amount of Cys was added in artificial urine and serum samples with a recovery of Tb3+/[G3T]5
ip t
luminescence exceeding 95%, which was promising in practical applications. Leung and Ma et al. reported a G-quadruplex DNA-5/Ir3+ complex 108/Hg2+ ensemble (Figure 62)
cr
[126] to detect Cys and GSH with a tunable concentration range by varying Hg2+ concentrations. 108
us
was weakly emissive. However, its luminescence was enhanced significantly in the presence of Gquadruplex DNA-5 by forming 108–G-quadruplex ensemble. Adding Hg2+ to the 108–G-quadruplex
an
ensemble significantly quenched the luminescence because of various ET mechanisms. Cys or GSH restored the luminescence signal of the 108–G-quadruplex ensemble because thiol functional groups
M
could remove Hg2+ ions effectively from the G-quadruplex DNA-5/108/Hg2+ ensemble by forming strong Hg2+–S bond.
d
Double-stranded DNA (ds-DNA) formed by T-Hg2+-T base pairs has recently been applied to detect
te
biothiols. Hepel and co-workers designed ssDNA-6 oligonucleotide (Figure 63) [127] with
Ac ce p
carboxyfluorescein dye 109 and quencher 110 appended at 5’ and 3’ ends, respectively, to detect Cys and GSH. These oligonucleotides exhibited self-hybridized T-T mismatch after adding Hg2+, which formed a T-Hg-T structure. The fluorescence of 109 was quenched due to FRET, from 109 to quencher molecule 110, because of their close proximity. Adding GSH or Cys dissociated T-Hg-T because Hg2+ strongly binds with GSH/Cys, which spatially separated fluorophore 109 from quencher 110 and enhanced the fluorescence of 109. Moreover, fluorescence intensity was higher in the presence of GSH than in the presence of Cys, which suggests that GSH binds Hg2+ more strongly than Cys because of the extensive steric hindrance of GSH. Tang reported a Thioflavin T (111)/T-Hg2+-T system for detecting biothiols (Figure 64) [128]. 111/DNA-7 displays strong emission in which 111 induces quadruplex folding. Upon on the addition of 37 Page 37 of 184
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Hg2+ ions, the G-quadruplex folding is inhibited by the Hg2+-mediated formation of T–T base pairs, making the 111 stay in a free state and a weak fluorescence can bedetected. When biothiols was added, the 111/G-quadruplex ensemble was re-formed because stronger Hg–S interaction leads to dissociation of T-Hg2+-T base pairs.
ip t
Yao and Sun et al. also employed T-Hg2+-T base pairs to design biothiols probe based on GO/Ru complex 112/DNA-8 assembly (Figure 65) [129]. In a GO/112/ssDNA-8 assembly, fluorescence of 112
cr
was quenched because of the strong interaction between 112 and GO as the quencher. Adding Hg2+
us
formed dsDNA-8 via T–Hg2+–T base pairs, and 112 intercalated into newly formed dsDNA-8. 112 and dsDNA-8 were then removed from the GO surface, which restored fluorescence. Subsequently, adding
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biothiols formed GO/112/DNA-8 assembly because of the high affinity of biothiol sulfur atoms to Hg2+.
M
T-Hg2+-T based pair was unwinded to produce ssDNA, which quenched the fluorescence of 112.
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4.2.1.2.2. Using the formation and dissociation strategy of polymer-Hg2+ complex
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Lee and coworkers proposed formed and dissociated conjugated polyelectrolytes 113−Hg2+−T assay
Ac ce p
to detect Cys (Figure 66) [130]. 113 exhibited a blue emission at 420 nm. A red emission at 653 nm was observed in the presence of Hg2+ and T, with decreased emission at 420 nm, which indicated intermolecular aggregates of 113 through the 113−Hg2+−T complex. This aggregation occurred because of the interactions of Hg2+ with 113 and Hg2+ with T, which formed T-Hg2+-T base pairs. Adding Cys reduced the red emission at 653 nm, and the blue emission was recovered at 420 nm, which suggests the dissociation of 113−Hg2+−T complex; Cys extracts Hg2+ from the assay complex through favorable binding between Cys and Hg2+.
Insert Figures 61-66 Herein
38 Page 38 of 184
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4.2.1.3. Silver Complexes 4.2.1.3.1. Introducing Ag+ binding sites into the polymer backbone
Bai et al. prepared Ag+ complexes of fluorescent conjugated polymers 114 and 115 (Figure 66)
ip t
[131], which contained 2,2’-biimidazole as coordination sites for Ag+, as ratiometric sensing platforms to detect Cys. 114-Ag+ and 115-Ag+ complexes decomposed upon the titration of Cys because Cys
an
4.2.1.3.2. Using the ensembling strategy of DNA and Ag+
us
cr
binds Ag+ through thiol–Ag+ interaction.
Luo and Li et al. [132], Hu and Zhou et al. [133-134] developed GO/DNA/Ag+ as a sensing platform
M
to selectively detect Cys from 19 other essential AAs. GO adsorbed cytosine (C)-rich unbound ssDNA9 and fluorescein derivative 109-labeled ssDNA-10 (Figure 67)132 by forming GO/DNA-9/DNA-10
d
complexes by stacking interactions between nucleotide bases and GO, which quenched the fluorescence
te
of 109. Fluorescence of 109 was significantly increased and red-shifted in the presence of Ag+ because
Ac ce p
of the formation of cytosine-Ag+-cytosine (C–Ag+–C) base pairs. C–Ag+–C structures unfolded upon adding Cys as a strong Ag+-binder and transformed dsDNA to two ssDNA, which were adsorbed on GO. Fluorescence was quenched, and the fluorescence emission wavelength was restored gradually. GO adsorbed C-rich fluorescein derivative 109-tagged ssDNA-11 (Figure 68) [133] and G-rich 109-tagged ssDNA-12 (Figure 68) [134] exhibited weak fluorescence because of FRET from 109/ssDNA-11 or 109/ssDNA-12 to GO. Introducing Ag+ recovered a large degree of fluorescence because of C–Ag+–C base pairs formation of 109/ssDNA-11 and G-Ag+ structure formation of 109/ssDNA-12; energy donor 109 was far from the GO surface, and FRET disappeared. Fluorescence of 109 was quenched again in the presence of Cys because FRET recovered from the strong binding between Cys and Ag+. The binding removed Ag+ from the C–Ag+–C base pairs, and the G-Ag+ structure 39 Page 39 of 184
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was destroyed. Shi et al. recently employed Tb3+/DNA-4/DNA-13/Ag+ sensing system to detect Cys (Figure 69) [135]. Luminescence of dsDNA/Tb3+ ensemble Tb3+/[G3T]5/C[G3T]5 was turned on in the presence of Ag+ because of the strong interaction of Ag+ with C[G3T]5. This interaction formed a C–Ag+–C
ip t
complex that liberated [G3T]5 from the [G3T]5/C[G3T]5 duplex and resulted in Tb3+/[G3T]5 luminescence. C–Ag+–C complex decomposed upon adding Cys because of the binding between Cys
cr
and Ag+, and fluorescence was quenched again. No obvious luminescence decrease was observed with
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the other AAs, which indicates that the Tb3++[G3T]5/C[G3T]5+Ag+ sensing system is suitable for
an
specific detection of Cys.
M
Insert Figures 67-69 Herein
4.2.1.4. Cobalt complexes
te
d
4.2.1.4.1. Introducing Co2+ binding sites into the polymer side chains
Ac ce p
Lee et al. reported Co2+-mediated hyperbranched polymer 116 as a sensing platform to detect Cys (Figure 70) [136]. Co2+ quenched the emission of 116 by forming 116–Co2+ complex through the interaction of Co2+ and sulfonic acid groups of 116. 116–Co2+ was dissociated to generate a favorable and strong Cys–Co2+ complex by adding Cys. However, Cys induced complete emission quenching of 116 instead of restoring its original fluorescence because of the absorption screening effect of the CysCo2+ complex, which prevents 116 from absorbing excitation energy.
Insert Figure 70 Herein
4.2.2. Using Chemodosimeter Approach 4.2.2.1. Iridium Complexes 40 Page 40 of 184
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Zhao, Huang, and coworkers [32] utilized water-soluble iridium complex-functionalized poly(Nisopropylacrylamide) 117 (Figure 71) in sensing Hcy and Cys from the interaction between aldehyde groups on 117 and thiol groups to form thiazolidine or thiazinane ring [137]. Among the various AAs,
ip t
only Cys and Hcy induced fluorescence enhancement with a blueshift from 567 to 558 and from 567 to 554, respectively. 117 can also be applied in quasi-solid state to sense Hcy and Cys, with visible color
cr
change from orange to yellow using polymer hydrogel.
us
Subsequently, Zhao, Huang, and coworkers developed another chemodosimeter for Cys and Hcy based on water-soluble phosphorescent polymer 118 (Figure 72) [138] by introducing an iridium
an
complex as a phosphorescent signaling unit. The design was based on the fact that iridium complex monomers contain aldehyde groups and could react with β- and γ-aminothiol groups to form
M
thiazolidine and thiazinane, respectively, which result in changes in emission intensity of the iridium
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Ac ce p
Insert Figures 71-72 Herein
d
complex, thereby facilitating the detection of Cys and Hcy.
4.2.2.2. Metal-Organic Frameworks (MOF)
Wang and Feng et al. recently synthesized a new metal–organic framework (MOF) 119-ZIF-90 (Figure 73) by linking malonitrile (119) to zeolitic imidazolate frameworks (ZIFs) [139]. 119-ZIF-90 is the first fluorescent MOF probe to detect H2S and selectively recognize Cys. Fluorescence of ZIF-90 quenched through intramolecular PET, which produced double bond linkages of 119 and ZIF-90. Fluorescence enhanced 3.3-fold and 8.5-fold upon immersing 119-ZIF-90 (0.2 mM) in a solution of H2S (0.2 mM) and Cys (0.2 mM), respectively, because of adding thiol compounds to α, β-unsaturated 119, which resulted in broken double bonds. Other AAs investigated in this work only exhibited small 41 Page 41 of 184
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fluorescence enhancement. The system was also applied to recognize biothiols in biological systems through fluorescence microscopy studies.
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Insert Figure 73 Herein
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5. Hybrid Organic-Metal Nanoparticles/Nanoclusters
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In the last decade, fluorescent/luminescent nanoparticles/nanoclusters [140-143] have emerged as a new class of fluorophores with the potential to overcome the limitations of conventional fluorophores,
an
such as photobleaching, limited brightness (the product of extinction coefficient and fluorescence quantum yield) and short lifetimes. By functionalizing the organic part on the metal nanoparticles, the
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surface chemistry of the nanoparticles can be tuned to create chemical specificity, which is a key
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requirement for successful sensing and imaging platforms [143].
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5.1. Small Molecule-Functionalized Metal Nanoparticles/Nanoclusters
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5.1.1. Using Binding Site-Signaling Subunit Approach 5.1.1.1. Gold Nanoparticles
Thomas et al. synthesized the photochromic spiropyran functionalized Au nanoparticles (Au-SP) (Figure 74) [144-145] for the assembly and release of an AA derivative upon irradiation. Under dark conditions, the majority of spiropyran molecules exist in their “closed” spiro form (SP, colorless and nonpolar), which when excited with UV light, undergoes photoisomerization to the “open” merocyanine form (MC, highly polar and zwitterionic) and absorbs in the visible region. Ring closure to the spiropyran form can occur either thermally or by exposure to visible radiation. After binding with charged AAs, the emission intensity of Au-MC decreased gradually with time, and the solution became 42 Page 42 of 184
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practically non-fluorescent after 120 min. The Au-MC/AA complex dissociates upon photoirradiation at 520 nm and undergoes thermal ring closure to Au-SP, releasing the AA derivatives. The complexation/dissociation cycles could be repeated many times. Light-mediated binding and the release of AA derivatives on the nanoparticle scaffold, in combination with the site specificity of the Au
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nanoparticle, offers a unique possibility of designing light-mediated controlled release systems. On the other hand, only a few AAs were studied, and the sensitivity and selectivity of Au-SP toward specific
us
cr
AAs were unknown.
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Insert Figure 74 Herein
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5.1.1.2. Quantum Dots
Semiconductor quantum dots (QDs) [146-149] have emerged as an attractive fluorescent material
d
over the past two decades. A comparison with organic dyes and fluorescent proteins revealed QDs to
te
have a high emission quantum yield, size-dependent wavelength tunability, broad excitation spectrum,
Ac ce p
narrow/symmetric emission spectrum, high photobleaching threshold and excellent photostability. These advantages make QDs ideal fluorescent indicators for chemical and biological assays. Previous studies of the interactions between QDs and metal ions reported that surface capping ligands had a profound effect on the luminescence response of QDs to physiologically important metal cations. Therefore, specific sensing of analytes can be achieved by the proper choice of QDs surface ligands. In 2009, He et al. prepared monodisperse and homogeneous mercaptoacetic acid (MAA)-capped CdSe/ZnS QDs (MAA-QDs) [150] for L-Cys detection. An increase in the fluorescence intensity of MAA-QDs was observed in the presence of L-Cys (10-800 nmol L-1). No interference to coexisting foreign substances including common ions, carbohydrates, nucleotide acids and other 19 AAs was observed. Moreover, their method has been applied successfully to the determination of L-Cys in 43 Page 43 of 184
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clinical and biological samples. In 2011, Wang et al. reported that the probe, sodium citrate (Cit)-capped CdS QDs [151], offered good sensitivity and selectivity for the detection of Cys. In the presence of Cys, the coordination of a mercapto group with Cd2+ through the formation of Cd-S bonds led to the adsorption of Cys onto the
ip t
surface of CdS nanocrystals, resulted in an increase in the fluorescence intensity of Cit-capped CdS QDs (4.0×10−5 M) with Cys from 1.0×10−8 M to 5.0×10−5 M. Another sulfur-containing AA, Met, as a
cr
control molecule, did not affect the fluorescence of Cit-CdS even at high concentrations. This is because
us
the sulfur atom in Met is flanked by a methyl group and amethylene group on the two sides, which hindered the interaction between Cd and sulfur. Moreover, other AAs (such as Arg and His) showed
5.1.2. Using Displacement Approach
d
5.1.2.1. Gold Nanoparticles/Nanoclusters
M
an
almost no interference on the detection of Cys at high concentrations.
te
Gold nanoparticles (Au NPs) have a high extinction coefficient in the visible region. These
Ac ce p
extraordinary optical features make Au NPs an ideal color reporting group for signaling molecular recognition events and making them function as efficient quenchers for most fluorophores [152-156]. Dong et al. reported a NIR fluorescent method [157], that can be used for the detection of thiols in plasma, which is based on a thiols-modulated interaction between NIR fluorescent dye 120 and Au NPs (Figure 75). The fluorescence emission of 120 was decreased dramatically in the presence of Au NPs with a 2 nm-blue-shift. This was attributed to ET because slight overlap between the emission spectra of 120 and the absorption spectra of the Au NPs. With increasing Cys concentration, the fluorescence intensity of 120 increased gradually due to the strong affinity of thiol to gold over a Au-N interaction that the adsorbed 120 was replaced by Cys. As a result, Cys was favorably capped on the surface of the Au NPs, and 120 was released to the solution. Hcy and GSH with thiol groups also produced an 44 Page 44 of 184
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enhanced fluorescence signal, whereas there was almost no observable change in fluorescence upon the addition of the other AAs without thiol groups. GSH exhibited a relatively low reaction activity compared with Cys and Hcy, which might be due to steric hindrance. Song and coworkers fabricated Ni2+-modified Au nanoclusters (NCs) to fluorescence turn-on
ip t
detecting His, in urine samples (Figure 76) [158]. Bovine serum albumin (BSA)-capping Au NCs emitted red fluorescence under UV light (365 nm). Fluorescence of BSA-Au NCs was quenched by Ni2+
cr
and restored by His. A nonfluorescence groundstate complex formed between Ni2+ with the BSA–Au
us
NC surface and the dissociation of Ni2+ from the Au NCs surface by coordinating His with Ni2+.
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Insert Table 2 and Figures 75-76 Herein
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5.1.2.2. Silver Nanoparticles
detect low and high molecular weight thiol-containing biomolecules
te
spheres (Figure 77) [159]
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Yu et al. reported that the formation of 121/Ag NPs/carbonaceous nanospheres (C NPs) hybrid
Ac ce p
selectively and sensitively, including Cys, GSH, dithiothreitol and BSA, upon a place-exchange process between 121 on the surface of the Ag NPs and the thiol groups of thiol-containing biomolecules. On the other hand, the fluorescence intensity of the solution remained unchanged in the presence of other AAs and monosaccharides, indicating that the amino and carboxyl groups in the AAs as well as the hydroxyl and aldehyde groups in the monosaccharides cannot effectively place exchange 121 molecules on the surface of the Ag NPs. Cys showed a significantly higher fluorescence ratio (F/F0), showing that the thiol functionality in Cys is essential for spectral changes.
Insert Figure 77 Herein
45 Page 45 of 184
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5.1.2.3. Quantum Dots
Wu and Yan synthesized Hcy-capped CdTe QDs (Figure 78) [160] through covalent binding of the thiol groups of Hcy with Cd2+ of CdTe core using the modified Rogach–Weller method [161-162]. Ni2+-
ip t
modulated Hcy-capped CdTe QDs based turn-on PL sensor was applied successfully to determine His in human urine samples. PL of Hcy-capped QDs was quenched rapidly upon adding Ni2+ because the
cr
coordination of Ni2+ with primary amine and the carboxylic group of Hcy eventually brought Ni2+
us
proximal to QDs, which resulted in a short range ET from excited Hcy-capped CdTe QDs to Ni2+. His restored the Ni2+-quenched PL of Hcy-capped CdTe QDs because of the high affinity of His to Ni2+,
an
which dissociated Ni2+ from the Hcy-capped CdTe QDs surface. The developed turn-on mode QD-based PL sensor had higher selectivity for His over the other AAs. Biothiol interference can be eliminated by
M
diluting samples or by blocking the biothiols with NEM.
Su’s group developed a simple and efficient fluorescence turn-on assay [163] to detect biothiols
d
(GSH and L-Cys), His, and threonine (Thr) in PBS buffer and in human serum samples based on an
te
indicator-displacement assay (IDA) and Cu2+–biothiols (GSH and L-Cys), His, or Thr affinity pairs
Ac ce p
(Figure 79). This approach employs Tyr-functionalized CuInS2 QDs (T-CuInS2 QDs) as indicators, and biothiols (GSH and L-Cys), His, or Thr were selectively detected based on the competition between indicator and biothiols (GSH and L-Cys), His, or Thr in binding with Cu2+. The competition of biothiols (GSH and L-Cys), His, or Thr with T-CuInS2 QDs for Cu2+ resulted in the fluorescence restoration of T-CuInS2 QDs; restoration ability followed this order: GSH > Cys > His > Thr. Su’s group employed the same strategy in designing a dopamine-functionalized CdTe QDs (DA QDs) as a fluorescence probe to determine L-His (Figure 80) [164]. The probe displayed fluorescence quenching in the presence of Ni2+. Ni2+-promoted fluorescence quenching was inhibited by adding His. Tian et al. utilized CdTe/CdS QDs-phen complex [165] for selective detection of PL turn-on of Cys and HCy (Figure 81). Phen induced fluorescence quenching of CdTe/CdS QDs because of the formation 46 Page 46 of 184
Edited May 11
of nonfluorescent complexes of CdTe/CdS QDs-Phen. Phen was displaced from the QDs surface after adding Cys or Hcy because of the strong affinity of Cys and HCy to CdTe/CdS QDs. The complex showed a good linear relationship between PL intensity of QDs and concentration of Cys (1 μM to 70 μM) and HCy (1 μM to 90 μM). Among AAs, proteins, metal ions, carbohydrates, nucleotides, and
ip t
thiol-containing compounds, only Cys and Hcy were able to increase fluorescence at a concentration of 0.8 mM, which demonstrates superior selectivity of the system for Cys and Hcy. Cys was determined in
cr
human serum samples to evaluate the applicability of the present sensing assay in biological samples.
us
The method provided good recoveries from 84.7% to 115.9%, which indicates reliability and practicality to detect cysteine in biological fluids.
an
Zhong, Li, and coworkers designed a fluorescent sensor to detect biothiols via ET between CdTe/CdS QDs and TiO2 NPs (Figure 82) [166]. The coupling of mercapto propionic acid (MPA)-
M
capped QDs with TiO2 quenches QDs fluorescence because of the covalent bonding between the terminal carboxyl group of MPA ligands and the Ti atom on the surface of TiO2 NPs, which induced
d
electron injection from QDs to TiO2. When thiols were introduced to the QD–TiO2 composite system,
te
quenched fluorescence of QD was switched on by replacing MPA on the QDs surface with thiols
pathway.
Ac ce p
because of the strong coordination of thiols with metal ions on the QD surface, which interrupted the ET
Insert Figures 78-82 Herein
5.2. Polymer-Functionalized Metal Nanoparticles/Nanoclusters 5.2.1. Using Binding Site-Signaling Subunit Approach 5.2.1.1. DNA-Templated Silver Nanoclusters
Few-atom, molecular-scale noble metal NCs are a class of emitters that simultaneously exhibit 47 Page 47 of 184
Edited May 11
bright, highly polarizable discrete transitions and possess good photostability and small sizes within biocompatible scaffolds [167-168]. Han and Wang reported fluorescent Ag NCs stabilized by ssDNA14 (5’-AATTCCCCCCCCCCCCAATT-3’) (DNA-14/Ag NCs) [169]. PL intensity of DNA-14/Ag NCs was quenched effectively by increasing biothiol concentration because of the formation of
ip t
nonfluorescent coordination complex between DNA-14/Ag NCs and biothiols, which resulted in a redshift in the emission wavelength. DNA-14/Ag NCs had high selectivity for biothiols because no
cr
quenching responses to the other 19 α-AAs were observed. Moreover, the method was successfully
us
detected thiols in human plasma samples, which suggests that the approach is practical for diagnostic purposes.
an
Ren, Xu et al. reported turn-on fluorescence of DNA-15 templated Ag NCs, dC12-Ag NCs, with increasing concentrations of thiol compounds (Cys, Hcy, and GSH) (Figure 83) [170]; the enhancement
M
followed the order, Hcy > GSH > Cys, which is parallel to the order of charge donating ability of thiol compounds. Turn-on fluorescence of dC12-Ag NCs by thiols was due to a charge transfer from the
d
ligands to the metal center via Ag-S bonds and to the contribution of other electron-rich groups (–
te
COOH, –NH2) in the thiol groups. Fluorescence enhancement is also due to changes in the
Ac ce p
microenvironment of the dC12 template because of addition of thiol compounds. By contrast, the other 19 AAs or biologically relevant analytes exhibited no obvious enhancement. The observed high specificity is due to specific and robust interaction between Ag and thiol compounds. Fluorescence response pattern of Ag NCs to a specific analyte significantly depends on the nature of the DNA template. Enhanced fluorescence was observed for Ag NCs formed in a series of polycytosine DNA (DNA-15, 16, 17, 18) upon adding thiol compounds; nearly no fluorescence variations of AgNCs formed in DNA-19 and DNA-20, and fluorescence of DNA-21, 22, 23, 24 templated AgNCs decreased (Figure 83).
Insert Figure 83 Herein 48 Page 48 of 184
Edited May 11
5.2.1.2. DNA-Templated Copper NanoClusters
Chu and coworkers reported dsDNA-templated Cu NCs as a fluorescence probe to detect biothiols
ip t
(Figure 84) [171]. PL intensity of DNA-CuNCs was quenched effectively by increasing biothiol concentration because of the formation of nonfluorescent coordination complexes between DNA-Cu
cr
NCs and biothiols. The resulting calibration plots exhibited good linear correlations from 2.0×10−6 to
us
1.0×10−4 M for Cys, 2.0×10−6 to 8.0×10−5 M for GSH, and 5.0×10−6 to 2.0×10−4 M for Hcy. The method
an
was successfully applied to detect biothiols in human plasma samples.
M
Insert Figure 84 Herein
5.2.2. Using Displacement Approach
te
d
5.2.2.1. Polymer-Templated Gold Nanoparticles/Nanoclusters
Ac ce p
Over the last decade, the application of Au NPs and water-soluble fluorescent polymers has attracted considerable attention due to their unique performance for use as highly sensitive chemical and biosensors [172-176]. The composited polymer-Au NPs have been appled in detecting AAs. Water-soluble anionic fluorescent conjugated polymer 122-stabilized Au NPs (122-Au NPs) (Figure 85) [177] was used to sensitively and selectively detect Cys. In this system, 122 not only functioned as a photoactive fluorophore, but also as a good protective agent for colloids because they can combine steric and electrostatic stabilization into electrosteric stabilization. Moreover, Au NPs did not aggregate from the steric effects of 122. The fluorescence of 122 was weak because of highly efficient FRET between 122 and Au NPs. Consequently, fluorescence of 122 was recovered by increasing Cys concentration because of the strong interaction between the thiol group of Cys and gold and 122 moved 49 Page 49 of 184
Edited May 11
away from the Au NP surfaces. The control experiments showed that Cys had a negligible effect on the emission of 122 alone. Therefore, increased fluorescence did originate from the modulation of ET between 122 and gold where 122 acted as an amplifier. Importantly, 122 contributed to the low LOD. Among the other 19 AAs, Met exhibited a relatively large increase in fluorescence because of the weak
ip t
interaction between the S-CH3 group and Au NPs. Fluorescence in the presence of the other 19 AAs all increased less than 5% relative to Cys at the same concentration (3.0 μM). Other thiol molecules (e.g.,
cr
2-mercaptoethanol and thioglycolic acid) also increased fluorescence intensity of the 122-Au NPs
us
solution, which suggests that the thiol group of Cys has an important role in the system. Guan et al. developed the sensitive and selective detection of Asp and Glu based on polythiophene
an
(123)-Au NPs composites (Figure 86) [178]. When a wine-red colored Au NPs solution was added to a yellow aqueous solution of 123, the fluorescence of 123 could be quenched dramatically by Au NPs,
M
even at very low concentrations through highly efficient ET between them. The KSV value was 1.29×1010 M−1 with concentrations ranging from 0 pM to 26 pM. Only Asp and Glu could recover the
d
quenched fluorescence of among 20 AAs investigated because of the acidic properties of Asp and Glu,
te
and 123 was released from the 123-Au NPs composites to emit fluorescence.
Ac ce p
Park and coworkers developed BSA-stabilized Au NCs as turn-on fluorescent sensors to detect biological thiol (Figure 87) [179]. Hg2+ ions quenched the red fluorescence of Au NCs via high-affinity metallophilic Hg2+–Au+ interactions. Biological thiols captured Hg2+ ions via a robust Hg–S interaction, which prevented Hg2+-induced quenching and resulted in Au NC fluorescence.
Insert Figures 85-87 Herein
5.2.2.2. Polymer-Templated Silver Nanoclusters
Shang and Dong produced water-soluble Poly(methacrylic acid, sodium salt) (124)-templeted Ag 50 Page 50 of 184
Edited May 11
NCs using as a fluorescent sensor for Cys (Figure 88) [180]. 124-stabilized Ag NCs displayed a maximum fluorescence emission at approximately 615 nm, which originates from the inter-band transitions from the submerged and quasi-continuum 5d band to the lowest unoccupied conduction band of the Ag NCs [181-182]. With increasing Cys concentration, the fluorescence emission of the 124-Ag
ip t
NCs decreased gradually and was almost completely quenched in the presence 6.0×10-5 M Cys with an obvious red-shift in the emission maximum. This was attributed to the thiol-adsorption-accelerated
cr
oxidation of emissive Ag NCs. The present assay allows for the selective determination of Cys in the
us
range of 2.5×10−8 to 6.0×10−6 M.
Luo and Li et al. synthesized water soluble polyethyleneimine 125-capped Ag NCs (Figure 88)
an
[183] that could selectively recognize thiols (i.e., Cys, Hcy, and GSH among 20 natural AAs, Hcy, and GSH) based on the interaction of silver ions with amino groups of 125. NCs agglomerated upon adding
M
thiols because the adsorbed biothiols on 125-Ag NCs freed the Ag NCs and lowered surface charge, which resulted in large nonfluorescent NPs with average diameters of 110 nm and various geometries.
d
Fluorescence intensity of 125-Ag NCs was gradually quenched by increasing biothiol concentration.
te
Linear ranges for Cys, Hcy, and GSH were 0.1 mM to 10 mM, 0.1 mM to 10 mM, and 0.5 mM to 6
Ac ce p
mM, respectively. Sensitivity (Cys, Hcy > GSH) was rationalized on the basis of steric effects on GSH chemisorption on 125-Ag NCs. 125-Ag NCs were further investigated for its ability to detect biothiols in human plasma samples.
Sun et al. applied human serum albumin (HSA)-stabilized gold-core silver-shell nanocrystals (HSAAu/Ag NCs) (Figure 89) [184] to determine the concentration of [Cys plus HCy] in spiked solutions of biomolecules and real biological samples. Adding Cys (or HCy) quenched NC luminescence because Cys or HCy adsorbed on the surface through ligand exchange with HSA.
Insert Figure 88-89 Herein
51 Page 51 of 184
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6. Chiral/Enantiomeric Recognition
AAs play undeniable roles in a wide range of bioscience areas and food analysis [185]. AAs can be present as L- or D-isomers. Although the D-amino acids (D-AAs) and L-amino acids (L-AAs) have
ip t
similar physical characteristics and chemical properties in nonstereo environments, they can have quite different pharmacological properties and bioactive effects in stereo environments, particularly in
cr
biological environments. This is why the U.S. Food and Drug Administration (FDA) has laid down
us
strict guidelines on the identification and quantification of chiral compounds [186-189]. Therefore, enantioselectivity is one of the most important goals for the sensing of organic substances [190-198],
an
because biological activity is strictly correlated with stereochemistry. Although some enantioselective methods based on capillary electrophoresis [199-200], voltammetry [201], colorimetric methods [202-
M
204] etc. have been proposed, there are examples of enantioselective fluorescence sensors [205-206]. Fluorescent sensors that can differentiate the two enantiomers of a chiral compound should provide
d
a real time technique for rapid chiral assays with many unique advantages compared with the ESI-MS
te
spectra, NMR, UV-Vis and electrophoresis [207-210]. The chiral recognition of AAs and peptides is a
Ac ce p
fundamental process for regulating various functions in living systems, particularly in connection with the application of high throughput combinatorial techniques [211]. Three possible methods achieve the chiral recognition of AAs in fluorescence/luminescence using fluorescent/luminescent sensors [212-215] that are generally composed of a fluorophore (indicator) and a binding site (receptor): (1) the introduction of chirality into the binding site of the sensor that could carry out the enantioselective recognition of chiral AAs; (2) labeling the chiral AAs with the fluorescence indicator that can be discriminated in the presence of the chiral receptor; and (3) the use of enantioselective indicator displacement assays.
6.1. Using Binding Site-Signaling-Subunit Approach 52 Page 52 of 184
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6.1.1. Introducing Chirality into the Binding Site of the Sensor 6.1.1.1. Introducing Chirality into Dansylated Cyclodextrins
Corradini et al. used dansylated cyclodextrins as tools for the development of enantioselective
ip t
fluorescent sensors of AAs or AA derivatives [216]. In these cyclodextrin derivatives, the ligands are terdentate, with an amide, amine, and sulphonamide group as Cu2+ binding sites. The Cu2+ ion may in
cr
turn act as a binding site for bifunctional moieties, particularly α-AAs. An additional chiral center was
us
present in the side arm, which could enhance the enantioselectivity. The dansyl group was selected as a fluorophore, which could interact with both the cyclodextrin cavity and Cu2+ ion.
an
In 2000, Corradini et al. reported that the fluorescence of two dansyl-modified cyclodextrins (R)126 and (S)-126 (Figure 90) [217] was quenched by forming non-fluorescent copper complexes, Cu-
M
(R)-126 and Cu-(S)-126, with the Cu2+ coordinated by the amino, amide and sulfonamide groups. An
d
increase in fluorescence was observed upon the addition of D- and L-AAs to Cu-(R)-126 and Cu-(S)-
te
126 at a 1:1 ratio. Complex Cu-(S)-126 showed better discriminating properties than Cu-(R)-126. In particular, Cu-(S)-126 was enantioselective for Pro, Phe and Trp. The best enantioselectivity of Cu-(S)-
Ac ce p
126 was observed for Pro with a reversed order (∆FD/∆FL=3.89) in the concentration range analyzed (6×10-5 M - 6×10-4 M). The enantioselectivity of Cu-(S)-126 for Pro was opposite to that observed for Phe (∆FD/∆FL=0.33) and Trp (∆FD/∆FL =0.63). A negligible difference was found between the two enantiomers of Ala, which bears a small aliphatic side chain, suggesting possible involvement of the cyclodextrin cavity in complex formation. In the case of His, a large increase in fluorescence was observed for both enantiomers on account of its strong histamine-like (amino and imidazolyl groups) binding sites. In 2004, the same research group examined the fluorescence sensing mechanism [218] of 126 as a function of the analyte AA and cyclodextrin structure. The enantioselectivity in the fluorescence response was attributed to the formation of diastereomeric ternary complexes. A comparison of 126 and the analogous compound 127, without a cyclodextrin part, provided important 53 Page 53 of 184
Edited May 11
insights into the role of the cavity in the recognition process. Based on the observation of 126, Corradini et al. then synthesized dansylated cyclodextrin derivatives (Figure 91) with rigid chiral side arms derived from AA synthons (AA = L- and D-phe (L126 and D-126), L- and D-phenylglycine (L-128 and D-128), L-pro (L-129), and L-cyclohexylglycine
ip t
(L-130)) [219] to increase the enantioselectivity. 128, 129 and 130 showed higher fluorescence than 126 under the same conditions, suggesting that a linker with a more rigid structure favors the self-inclusion
cr
of the dansyl group within the cyclodextrin cavity or provides a higher shielding effect of the
us
fluorophore, which is quite promising for the overall sensitivity of the sensing process. The enantioselectivity was evaluated by the addition of Cu2+ complexes of D- or L-val and D- or L-pro. The
an
L-AA containing cyclodextrins exhibited better enantioselectivity than D-AA containing cyclodextrins, some of which were higher than those already reported for 126. L-126, L-128, L-129 and L-130 showed
M
significant enantioselectivity in the fluorescence responses of both Pro and Val. The enantioselectivity was reversed for the two AAs (FL < FD for Pro and FL > FD for Val). The best enantioselectivity was
d
obtained with 130 for Pro and with 129 for Val, indicating that the insertion of more rigid and sterically
te
constrained structures (cyclohexylglycine and Pro) in the side arm is an efficient strategy for improving
Ac ce p
the enantioselectivity. Overall, the formation of a ternary diastereomer and the biasing effect of the cyclodextrin cavity in these chiral selectors were proposed [219]. The rapid, simple and low-cost technology of fluorescence microplate readers was also used to screen the samples with high enantiomeric excess using 128 [220].
Insert Table 3 and Figures 90-91 Herein
6.1.1.2. Introducing Chiral Molecules as Binding Sites
Xu and coworkers synthesized salan probe 131 to detect α-AAs (Figure 92) [221]. Fluorescence of 54 Page 54 of 184
Edited May 11
131 enhanced in the presence of CuCl in ethanol, which was attributed to Cu+-triggered π–π interaction of aromatic rings on 131 and formation of 131-Cu+ complex. In situ generated CuCl complex of 131 interacted with D/L-Leu and D/L-Pro via the Cu+ center, which decreased excimer fluorescence intensity. In situ generated CuCl2 complex of 131 enantioselectively recognized D-leucine (Leu) and L-
ip t
Leu through turn-on (D-Leu) and turn-off (L-Leu) fluorescence response mode. Fluorescence of
cr
Cu(OAc)2–131 complex was also enhanced in the presence of Phe and Pro AAs.
us
6.1.1.3. Introducing Chirality into Quantum Dots
an
Xia and coworkers reported a fluorescent sensory system to discriminate L-/D-Cys (Figure 93) [222] based on the assembly formation between D-Cys (or L-Cys) modified CdTe@CdS QDs (L-QDs
M
or D-QDs) NPs and gold nanorods (GNRs). L-QDs or D-QDs mixed with GNRs emitted strong fluorescence in NIR wavelengths. Cys induced efficient FRET from QDs to GNRs through the
d
formation of QD-GNR assembly, which quenched the fluorescence intensity of QD/GNR.
te
Enantiodiscrimination of Cys was observed through different quenching degrees of fluorescence. In
Ac ce p
practice, L-QD/GNR-based sensors exhibited distinct enantioselectivity to Cys, whereas D-QD-GNR exhibited reversed enantioselectivity to Cys (i.e., L-Cys quenched D-QD-GNR fluorescence stronger than D-Cys did). The results demonstrate that heterochiral (L- and D-Cys) interaction results in more notable FRET efficiencies compared with homochiral (L−L or D−D-Cys) interaction. The mechanism of QD/NR assemblies was confirmed further because thiol-free AAs and small thiol molecules led to a small decrease or no decrease in fluorescence. Moreover, the present sensing platforms determined both enantiomeric composition and concentration of Cys.
Insert Figures 92-93 Herein
55 Page 55 of 184
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6.1.2. Labeling Amino Acids Enantiomers with the Fluorescence Indicator
Lv et al. reported fluorescent water-soluble L-GSH-stabilized Ag NCs [223] for chiral recognition of D- and L-Cys based on effective PET between Ag NCs and L-Cys. Fluorimetric titration experiments
ip t
demonstrated that L-GSH–Ag NCs displayed excellent performance on enantioselective discrimination among enantiomers of Cys. For example, obvious fluorescence quenching of Ag NCs was observed in
cr
the presence of L-Cys. However, adding D-Cys scarcely influenced Ag NCs fluorescence. The
an
6.2. Using Enantioselective Indicator Displacement Assays
us
discrimination concentration limit between L-Cys and D-Cys was approximately 5 mM.
M
The fluorescence of perazamacrocycle 132 (Figure 94) [224], was quenched by Cu2+ through the formation of complex 132-Cu2+ with 1:1 stoichiometry and an association constant of 1.25×106 M-1. The
d
enantioselectivity of 132-Cu2+ toward Phe, Ala, Val and Pro was investigated due to the strong
te
association of Cu2+ with AAs that displaced 132 in the 132-Cu2+ complex [225]. Taking the recognition
Ac ce p
of Phe enantiomers as an example, both D-phe and L-phe induced apparent fluorescent enhancement responses by titrating the enantiomers of Phe to a mixture of 132 and Cu2+ (molar ratio of 132/Cu2+ was 1/2), whereas D-Phe was more effective than L-phe. The fluorescence of 132-Cu2+ (10 μM/10 μM) was enhanced 14.9-fold in the presence of D-phe (0.1 mM). Aswathy and Sony recently reported fluorescein (133)-(β-cyclodextrin)-Au NP assembly (Figure 95) [226] for FRET-based chiroselective turn-on sensing of Trp, Phe, and Tyr. 133 binds to the βcyclodextrin cavity with Ka=360 M−1 in the 133-(β-cyclodextrin)-Au NP assembly. FRET occurred from donor 133 to Au NP acceptor, which resulted in fluorescence quenching of 133 at 520 nm. 133-(βcyclodextrin)-Au NP assembly displayed high enantioselectivity to enantiomers of Trp, Phe, and Tyr. Upon addition of L-Trp, L-Phe, and L-Tyr to the assembly, the intensity of 133 increased in the 56 Page 56 of 184
Edited May 11
following order: L-Trp ＞ L-Phe ＞ L-Tyr. The FRET effect was inhibited because of the favored interaction of the phenyl ring with the β-cyclodextrin receptor, which expelled 133 from the βcyclodextrin cavity.
ip t
Insert Figures 94-95 Herein
us
cr
7. Pattern Recognition
The development of fluorescent/luminescence receptors for AAs with high selectivity is still a
an
challenge because of the structural similarity of the various AAs. Selectivity was achieved mainly by using receptors that could recognize a certain functional group of an AA side chain (e.g., imidazole of
M
His, thiol of Cys or carboxylate of Asp or Glu). On the other hand, a single-sensor approach would have trouble distinguishing simple, nonfunctionalized AAs, such as Ala or Val, due to the lack of sufficiently
d
specific receptors. An array-based approach would be suitable for achieving the required selectivity.
te
Pattern recognition is a very powerful tool because it can analyze a wide range of chemical
Ac ce p
structures and complex mixtures [227-231]. The IDAs approach, which relies on competition between an indicator and the analyte of interest for the binding site of a receptor, has been used to quantify a range of analytes, in which the receptor should have specific selectivity and sensitivity toward the analytes [232]. For the IDAs in the pattern recognition methods, a synthetic receptor does not need to exhibit specific or very selective binding to a target analyte. Instead, the receptors in the array only need to bind differently to various analytes, thereby creating a range of patterns for the analytes. Nevertheless, some degree of rational design is still effective for differential receptors because the receptors must have some affinity to the analytes, as well as some selectivity. The multi-analyte differential analyses with discrimination based on the molecular structure (chemoselectivity) and absolute configuration (enantioselectivity) was achieved using a pattern 57 Page 57 of 184
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recognition technique. The use of the less expensive and more commonly used instruments, such as UVVis spectroscopy [233-235] or fluorescence spectroscopy allows easy conversion to high-throughput screening (HTS) methods through the incorporation of a microplate reader, which allows rapid analysis of multiple samples.
ip t
UV-Vis spectra have been utilized to pattern recognition of natural AAs. For instance, in 2005, Buryak and Severin reported that the 20 natural AAs could be discriminated using an IDA-based assay
cr
with high fidelity by UV-Vis spectra in combination with multivariate analysis (Figure 96) [236]. The
us
UV-Vis response at 750 nm of an IDA composed of complex 134 (50 μM) and 135 (100 μM) was used to classify the AAs (750 μM) into a high-affinity group (Group I) consisting of His, Cys, methionine
an
(Met), Asp and asparagine (Asn), for which almost quantitative replacement of indicator 135 from complex 134 was observed (∆A(750 nm) < 0.06), and a low-affinity group (Group II) consisting of the
M
remaining 15 AAs showing partial replacement of the dye (0.55 > ∆A(750 nm) > 0.06). Each member of Group I was analyzed using the four IDAs (two indicators, 136 and 137, and two different pH values),
d
whereas each member of Group II was analyzed using five IDAs (indicator 135 at five different pH
te
values). All analyses were repeated 12 times with all data being collected in a highly parallel manner
Ac ce p
using a microplate reader. Using the pattern recognition approach, only Val and isoleucine (IIe) showed some overlap; the cyclic AA, Pro, was well separated from the rest; the hydroxy AAs, such as Ser and Thr, and the aromatic AAs, such as Phe, Tyr, and Trp, were positioned in proximity to each other; the closely related AAs, such as Leu and IIe, are clearly distinguishable, which would be very difficult to achieve using a classical one sensor-one analyte approach. As another example, in 2006, Anslyn et al. reported that a series of enantioselective IDAs, Cu2+ complexes of bidentate N-donor ligands 138-140 and 141-143, could be used as receptors and indicators, respectively (Figure 97) [237]. The selected indicators undergo large red shifts in their absorbance spectra upon metal coordination. The absorption and visual color of the indicators were recovered after adding the AAs analytes. The recovery was dependent on the ratio of AAs bound to the free indicator 58 Page 58 of 184
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and the stability of the receptor-AA complex. A two-dimensional plot (PC1 axis and PC2 axis) was given that could be used to identify the diagnostic patterns present in the array. All the AAs investigated were ordered chemoselectively along PC1, with scores inversely related to the sequence of the affinities for the receptor complexes. The chiral information is expressed predominantly along PC2, with negative
ip t
scores for D-AAs and positive scores for L-AAs. The aliphatic AAs (Leu, Val, Ile), which vary only by the side chain methylene groups, were separated clearly.
cr
A literature survey reveals that less attention was paid to the pattern recognition of AAs by the
us
fluorescence/luminescence metal-organic systems. The fluorescence ratiometric probes of BSA-AuNCsmetal (Figure 98) [238] provide a sensory method for the identification of AAs. BSA-AuNCs exhibited
an
dual emissions: blue emission at 425 nm from the oxides of BSA and red emission at 635 nm from the AuNCs. The BSA-AuNCs can interact effectively with many metal ions, such as Ni2+, Pb2+, Zn2+ and
M
Cd2+, due to the large amount of residual amino, carboxylic and mercapto groups, and disulfide bridges at the peptide chains of BSA. The fluorescence responses of BSA-AuNCs to metal ions were quite
d
specific: Ni2+ quenched both the fluorescence intensities at 425 nm and 635 nm, with a quenching
te
efficiency of emission at 425 nm and 635 nm of 70% and 82%, respectively. Pb2+ quenched the
Ac ce p
emission of the oxides of BSA significantly and the red emission changed slightly. In contrast, Zn2+ and Cd2+ enhanced the emission at 635 nm with a slight blueshift to 630 nm, whereas the emission at 425 nm showed a slight change. The metal ion-modulated BSA-AuNCs showed a ratiometric response to specific AAs. BSA-AuNCs-Ni2+ showed ratiometric fluorescence response after the addition of His with the emission at 635 nm enhanced significantly and the emission at 425 nm from the oxides of BSA changed only slightly. The fluorescence ratio of BSA-AuNCs-Pb2+ between 425 nm and 635 nm was increased by the presence of Asp. The ratiometric fluorescence response of BSA-AuNCs-Zn2+ and BSA-AuNCs-Cd2+ was observed in the presence of Cys and Asp. BSA-AuNCs-Ni2+, as an example, is quite sensitive to His but other AAs also affect the ratio of the dual emissions intensity because they can also coordinate with Ni2+, even though the effect is much weaker than His. On the other hand, the 59 Page 59 of 184
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responses of some AAs, such as Cys, Ala and Gln, are similar to each other. This makes it impossible to discriminate the various AAs using a single probe. Therefore, BSA-AuNCs-Ni2+, BSA-AuNCs-Pb2+, BSA-AuNCs-Zn2+ and BSA-AuNCs-Cd2+ were used as a fluorescence ratiometric sensor array to identify the various AAs by easy recognition of the signal patterns of the ratiometric fluorescence. The
ip t
addition of AAs (100 mM) resulted in a variety of fluorescence ratiometric responses. For example, Ala could not be identified from Cys in the BSA-AuNCs-Ni2+ system because they exhibit similar
cr
fluorescence responses but have different patterns in the array. Ala does not affect the ratio of BSA-
us
AuNCs-Cd2+ and BSA-AuNCs-Zn2+ in this sensor array, and is different from Cys. Therefore, Ala and Cys can be discriminated easily by the array, whereas it is impossible through a single probe. Other AAs
an
also have their distinct responses, and these responses are expected to identify a range of AAs as a
M
fingerprint.
te
Ac ce p
8. Conclusions
d
Insert Figure 96-98 Herein
Metal-organic fluorescent/luminescent systems of different types that sense AAs have been devised and the recognition mechanisms of these systems have been studied in detail in the recent past. Among them, it is still a challenge to both selectively and sensitively discriminate AAs, owing to the similarity in the structure and reactivity of some AAs. Although additional coordination with other groups in the AA’s side chains, such as His and Phe, etc., has sometimes resulted in some preferential coordination, better reporters are still rare. In this case, pattern recognition is a very powerful tool because it can analyze diverse chemical structures and complex mixtures. The discrimination of AAs in stereo environments is very important, particularly in biological environments because D-AAs and L-AAs have
very
different
pharmacological
properties
and
bioactive
effects.
The
use
of
60 Page 60 of 184
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fluorescent/luminescent metal-organic systems for chiral and pattern recognition of AAs is still in its infancy. Significant progress has been made in chemosensor or chemodosimeters for AAs, such as His and Cys, over the past fifteen years. On the other hand, fluorescent/luminescent chemosensors or
ip t
chemodosimeters for the specific detection of Gly (glycine), Lys (lysine), Met, IIe, Leu, etc., based on metal-organic systems, have not been reported. Therefore, considerable research will be needed to
cr
develop better chemosensors or chemodosimeters for the detection of these AAs.
us
There is much research needed in order to develop better sensing systems for the detection of natural AAs in vitro and in vivo applications. For example, the most involved recognition is employed
an
successfully in organic solvents but not water. This confines these sensors to be used for recognition in biological applications; most fluorescent/luminescent detectors for AAs are based on the measurements
M
at a single wavelength, which might be affected by variations in the sample environment. In contrast, ratiometric fluorescent probes allow measurements of the emission intensities at two wavelengths,
d
which should provide a built-in correction for environmental effects. Moreover, a NIR optical response
te
(e.g., 700 to 900 nm) is ideal for therapeutic applications and suitable for use as tags or stains for bio-
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imaging. In addition, it offers additional advantages over the visible optical response, such as lower interference of auto-fluorescence from endogenous chromophores and deeper penetration of tissues. The development of fluorescent/luminescent probes, based on metal-organic systems is progressing gradually, so we are convinced that more selective, more specific and more practical probes for natural AAs could be designed in the not-too-distant future.
ACKNOWLEDGMENT
This work was financially supported by National Natural Science Foundation of China (Grant No. 31360020), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State 61 Page 61 of 184
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Education Ministry ([2014]1985), Guangxi Natural Science Foundation (No. 2014GXNSFCA118003), Scientific Research Foundation of Guangxi University (Grant No. XGZ130080 and XGZ130081), and grants funded by Opening Project of Guangxi Key Laboratory of Petrochemical Resource Processing and Process Intensification Technology (No. 2013K002) as well as Foundation for Fostering Talents of
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Department of Chemistry & Chemical Engineering, Guangxi University (Grant No. 2013102).
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FIGURE CAPTIONS
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Table 1. Summary of fluorescent/luminescent amino acid sensors based on organic-metal complexes
nanoparticles/nanoclusters
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Table 2. Summary of fluorescent/luminescent amino acid sensors based on hybrid organic-metal
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Table 3. Summary of chiral recognition of AAs using fluorescent/luminescent sensors
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Figure 1. Chemical structures of compound 1 [38] and zinc complexe of 2 [39]. Figure 2. Chemical structures of compounds/zinc complexes of 3-7 [40-42]. Figure 3. Chemical structures of Zn(8) and Zn(9) [43]. Figure 4. Chemical structures of 10-12 [44]. Figure 5. Proposed binding mechanism of 13 and L-His [45]. Figure 6. Chemical structure of (Cu2+)2(14) [46] and 15 [47] and the reaction of (Cu2+)2(14) with Cys and His. Figure 7. The proposed binding mechanism of [Ir(16)]+ with His [48]. Figure 8. Chemical structures of 17, 18, 19 and time-dependent reaction of 17 with Cys [49]. Figure 9. Chemical structures of 20, 20-Au+, 21 and proposed binding mechanism of 20-Au+ with Cys 74 Page 74 of 184
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[50]. Figure 10. Chemical structures of Ce(22) [51] and 23 [53]. Figure 11. Chemical structure of 24 and the reaction mechanism of 24 with Ag+, Fe3+, and Cys [54]. Figure 12. Chemical structure of 25 [55].
Figure 14. Proposed mechanism for response of Zn(28) to Cys [58].
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Figure 15. Proposed mechanism for response of Zn(29) to Cys and His [59].
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Figure 13. Chemical structures of Zn(26) [56], 27 [57], 30 [60], 31 [62].
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Figure 16. Chemical structures of 32 and 33 [66]. Figure 17. Proposed mechanism for response of 34-Cu2+ to Cys [6].
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Figure 18. Proposed mechanism for response of 35-Cu2+ with Cys and His [67]. Figure 19. Chemical structures of 36, rhodamine B, and schematic illustration of Cys detection [68].
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Figure 20. Chemical structures of 37 [69], 38 [70], 37-Cu2+ and 38-Cu2+. Figure 21. Chemical structures of 39, 39-Cu2+ [71] and 40 [72].
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Figure 22. Chemical structures of 41, 42-Cu2+ and 42 [73].
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Figure 23. Chemical structures of 43 and 43-Cu2+ [74].
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Figure 24. Chemical structures of 44 [75] and 45 [76]. Figure 25. Chemical structures of 46 [77], 47 [78], and proposed sensing mechanisms for thiols. Figure 26. Chemical structures of 48 and 48-Hg2+ [79]. Figure 27. Chemical structures of 49 and 49-Hg2+ [80]. Figure 28. Chemical structures of 50 and 50-Hg2+ [81]. Figure 29. Schematic illustration of Hg2+ induced aggregation of 51 [82], 52 [83] and aggregate dissociation in the presence of Cys. Figure 30. Schematic illustration of Cys detection based on reduced graphene oxide (rGO)–53-Hg2+ ensemble [84]. Figure 31. Chemical structures of 54 [85] and 55 [86]. 75 Page 75 of 184
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Figure 32. Chemical structures of 56, 56-Cd2+ and proposed sensing mechanism of 56-Cd2+ for Cys [87]. Figure 33. Chemical structures of 57 and 57-Al3+ [88]. Figure 34. Reaction mechanism of 58, 59 and 60 with amino acids (AAs) [89]. Figure 35. Reaction of 61 with Cys [90].
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Figure 36. Chemical structures of 62, 63 and reaction mechanism of 63 with Cys and Hcy [92]. Figure 37. Chemical structures of 64-67 [93].
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Figure 38. Chemical structures of 68 [94], 69 and reaction mechanism of 69 with Cys and Hcy [95].
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Figure 39. Cys/Hcy sensing mechanism of 70 [96]. Figure 40. Cys/Hcy sensing mechanism of 71 [97].
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Figure 41. Chemical structures of 72, 73 and Cys/Hcy sensing mechanism of 72 [98]. Figure 42. Schematic illustration of reaction of 74 with Cys/Hcy and Trp [100].
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Figure 43. Reaction of 75 with Cys yielding 76 [101].
Hcy [102].
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Figure 44. Chemical structures of 77, 78, 79 and schematic illustration of reaction of 77 with Cys and
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Figure 45. Proposed reaction mechanism of 80 with thiols [31].
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Figure 46. The proposed reaction of 81 with sulfhydryl-containing AAs/peptides [105]. Figure 47. Chemical structures of 82, 83 and thiol sensing mechanism of 82 [106]. Figure 48. Chemical structures of 84, 85 and thiol sensing mechanism of 84 [107]. Figure 49. Schematic illustration of reaction of 86 with Cys and Hcy [108]. Figure 50. Reaction mechanisms of 87-90 with Cys and Hcy [109]. Figure 51. Chemical structure of 91 [110]. Figure 52. Schematic illustration of the detection mechanism of thiol using 92-Cu2+ in aqueous media [111]. Figure 53. Schematic illustration of the detection mechanism of thiol using 94-Cu2+ in aqueous media [112]. 76 Page 76 of 184
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Figure 54. Principle of a fluorescence assay for AAs using Cu2+ complexes of 96-99 [113-115, 117]. Figure 55. Chemical structure of 100, reaction mechanisms of 100-Cu2+ for Cys and 100-Ni2+ for His/Trp [118]. Figure 56. Chemical structures of 101 [119], 102 [119], 103 [120] and reaction mechanisms of 101-
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Cu2+ and 102-Cu2+ with AAs. Figure 57. Chemical structure of 104 and proposed sensing mechanism of 104-Cu2+ with His [121].
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Figure 58. Schematic illustration of the 105/DNA-1/metal ion-based AA sensor [122].
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Figure 59. Schematic illustration of His detection using DNA-2/106/Cu2+-based ensemble system [123]. Figure 60. Schematic illustration of DNA-3/Cu2+/107 ensemble with His and Cys [124].
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Figure 61. Schematic illustration of the detection mechanism of biothiols using Tb3+/DNA-4/Hg2+ ensemble [125].
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Figure 62. Schematic illustration of Cys detection using DNA-5/108/Hg2+-based ensemble [126]. Figure 63. Schematic illustration of Cys and GSH detection using DNA-6/Hg2+-based ensemble [127].
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Figure 64. Schematic illustration of bithiols detection using DNA-7/111/Hg2+-based ensemble [128].
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Figure 65. Schematic representation of thiols detection based on GO/112/DNA-8 assembly [129].
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Figure 66. Chemical structures of 113 [130], 114 and 115 [131]. Figure 67. Schematic representation of Cys detection based on GO and silver-specific DNA-9 and DNA-10 [132].
Figure 68. Schematic representation of Cys detection based on GO/DNA-11 [133] and GO/DNA-12 [134].
Figure 69. Schematic illustration of Cys detection based on Tb3+/DNA-4/DNA-13/Ag+ sensing system [135]. Figure 70. Chemical structure of 116 [136]. Figure 71. Schematic illustration of reaction of 117 with Cys and Hcy [32]. Figure 72. Schematic illustration of reaction of 118 with Cys and Hcy [138]. 77 Page 77 of 184
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Figure 73. Schematic illustration of Cys detection based on metal–organic framework [139]. Figure 74. Schematic representations of the photochemical ring opening and closing of Au-SP in the absence and in the presence of AAs [144-145]. Figure 75. Schematic illustration of Cys detection based on Au NPs/120 system [157].
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Figure 76. Schematic illustration of His detection based on Ni2+-modified Au NCs [158]. Figure 77. Schematic illustration of thiols detection based on 121/Ag NPs/carbonaceous nanospheres
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(C NPs) hybrid spheres [159].
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Figure 78. Schematic illustration of His detection based on Hcy-capped CdTe quantum dots (QDs) [160].
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Figure 79. Schematic illustration of AAs detection based on Tyr-functionalized CuInS2 QDs [163]. Figure 80. Schematic illustration of His detection based on dopamine-functionalized CdTe QDs [164].
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Figure 81. Schematic illustration of His detection based on CdTe/CdS QDs-Phen complex [165]. Figure 82. Schematic illustration of thiols detection via inhibition of electron transfer between
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CdTe/CdS QDs and TiO2 NPs [166].
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template [170].
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Figure 83. Fluorescence response pattern of Ag NCs to thiols depends on the nature of the DNA
Figure 84. Schematic illustration of biothiols detection based on DNA-25/DNA-26/Cu NCs [171]. Figure 85. Schematic illustration of the detection mechanism of Cys using 122-stabilized Au NP [177]. Figure 86. Schematic illustration of the detection mechanism of Asp and Glu using 123-Au NPs composites [178].
Figure 87. Schematic illustration of the detection mechanism of thiols using BSA-stabilized Au NCs [179]. Figure 88. Chemical structures of 124 [180], 125 and proposed sensing mechanism of thiols using 125capped Ag NCs [183]. Figure 89. Schematic illustration of the detection mechanism of Cys and Hcy using HSA-stabilized 78 Page 78 of 184
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Au/Ag NCs [184]. Figure 90. Chemical structures of Cu-(R)-126, Cu-(S)-126, and 127 [217]. Figure 91. Chemical structures of the dansylated cyclodextrin derivatives 126, 128-130 [219]. Figure 92. Reaction mechanisms of 131-Cu+ and 131-Cu2+ for α-AAs [221].
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Figure 93. Schematic illustration of L-/D-Cys detection based on D-Cys (or L-Cys) modified CdTe@CdS QDs [222].
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Figure 94. Chemical structure of complex 132-Cu2+ [224].
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Figure 95. Schematic illustration of AAs detection based on 133-(β-cyclodextrin)-AuNP assembly [226].
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Figure 96. Colorimetric identification of 20 natural AAs using IDA arrays composed of receptor 134 and the indicators 135-137 at different pHs [236].
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Figure 97. Ligands 138-140 and indicators 141-143 used to construct sensor array [237].
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BSA-Au NCs-metal [238].
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Figure 98. Schematic illustration of AAs identification based on fluorescence ratiometric probes of
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Table(s)
λex/λem (nm)
Specificity
Condition
Detection limit
Ref.
1–Zn2+
–/413
Trp
dioxane/H2O (4:1, v/v), pH 6.8
–
38
2
347/454
His
MeOH/H2O (6:4, v/v), pH 6.8
0.134 µM
39
3–Zn2+
370/430
–
–
–
40
4–Zn2+
398/510
–
–
–
41
2+
350/383
–
–
–
42
8–Zn2+
320/525
Arg
HEPES buffer, pH 7.4
2.05 µM
43
10–Zn2+
343/400
His
HEPES with 1% THF, pH 7.35
–
44
13
298/352
His
HEPES buffer, pH 7.35
–
45
14–Cu2+
350/552
His, Cys
HEPES buffer, pH 7.4
–
46
15–Cu2+
457/476,537
His
EtOH/HEPES buffer (6:4, v/v), pH 7.2
5 µM
47
[Ir(16)]+
350/505
His
PBS buffer
–
48
17
DMF/HEPES buffer (9:1, v/v), pH 7.0
1.26 µM
49
MeOH/H2O (1:99, v/v)
0.1 µM
50
DMF/H2O (7:3, v/v), pH 5.0–9.0
37.4 µM
51
cr
us
6–Zn
ip t
Complex
an
Table 1. Summary of fluorescent/luminescent amino acid sensors based on organic-metal complexes
Cys
500/560
Cys
Ce(22)
350/470
Trp
23–Al3+
390/470
His
HEPES buffer, pH 7.7
0.3 µM
53
24–Ag+
344/377,470
Cys
EtOH/H2O (1:9, v/v)
–
54
24–Fe3+
344/377,470
Cys
EtOH/H2O (1:9, v/v)
–
54
25
423/657
His
Tris/HCl buffer, pH 8.0
2 µM
55
26–Zn2+
320/440
–
–
–
56
27–Zn2+
320/444
–
–
–
57
2+
390/454
Cys
MeOH/HEPES buffer (2:1, v/v), pH 7.4
392(±23) ppb
58
28–Zn2+
390/454
biological thiol
reduced blood serum
846 ppb
58
390/454
Cys+His
EtOH/HEPES buffer (2:1, v/v), pH 7.4
–
59
360/495
His
MeOH
0.33 ppm
60
360/535
Cys
MeOH
0.42 ppm
60
30-Co2+
360/535
–
–
–
60
30-Mn2+
360/535
–
–
–
60
30-Ni2+
360/535
–
–
–
60
2+
350/550
His
CH3CN/HEPES buffer (1:1, v/v), pH 7.4
–
62
[Cu2(32)]4+/33
–/540
His
HEPES buffer, pH 7
–
66
34-Cu2+
670/850
Cys
DMF/human plasma
4.07 µM/4.37 µM
6
29–Zn2+ 30–Zn2+ 30-Cu2+
31-Zn
ed
ce pt
28–Zn
Ac
20–Au
M
450/504 +
Page 179 of 184
330/550
Cys/His
HEPES buffer, pH 7.4
–/–
67
36-Cu2+
560/583
Cys
EtOH/Tris-HCl buffer (4:6, v/v), pH 7.1
0.14 µM
68
37-Cu2+
410/500
His
HEPES with 0.5% DMSO, pH 7.4
3.1 µM
69
38-Cu2+
–/480
His
CH3CN/HEPES buffer (1:5, v/v), pH 7.4
–
70
39-Cu2+
496/502
Cys/Hcy
CH3CN/HEPES buffer (1:1, v/v), pH 7.4
0.17/0.25 µM
71
40-Cu2+
325/434,494
Cys
DMSO/HEPES buffer (1:9, v/v), pH 7.4
0.541 µM
72
42-Cu2+
305/482
Cys/Hcy/GSH
CH3CN/HEPES buffer (1:5, v/v), pH 7.4
–/–/–
73
43-Cu2+
418/541
Cys/Hcy/GSH
EtOH/HEPES buffer (9:1, v/v), pH 7.4
0.42/0.105/4.34 µM
74
44-Ag+
285/315,445
Cys
MeOH
514 ppb
75
45-Ag+
280/390
–
–
–
76
46-Hg2+
–/678
thiol AAs
CH3CN/H2O (2:1, v/v)
–
77
47-Hg2+
630/664
Cys
EtOH/H2O (3:7, v/v)
36.7 nM
78
48-Hg2+
324/436
Cys
HEPES with 1% DMSO, pH 7.4
9.6×10−11 M
79
49-Hg2+
488/520
Cys
CH3CN/H2O
1.60×10−8 M
80
50-Hg2+
350/401
Cys
DMSO/H2O (1:9, v/v)
–
81
51-Hg2+
484/532
Cys
DMF/H2O (9:1, v/v)
9.6 nM
82
52-Hg2+
562/591
Cys
THF/H2O (2:1, v/v)
91.3 nM
83
rGO–53-Hg2+
490/540
–
–
–
84
54-Hg2+
500/582
L-pro
MeCN/Tris-HCl buffer (1:1, v/v), pH 7.2
–
85
55–Hg2+
330/512
19 α-AAs
aqueous solution, pH 6.5
–
86
56–Cd2+
380/456
Cys
MeOH
58 ppb
87
57-Al3+
500/579
Arg
MeOH/Tris-HCl buffer (9:1, v/v), pH 7.0
2.3 µM
88
58
467/
sulfhydryl AAs
DMF-phosphate buffer (1:1, v/v), pH 7.0
–
89
59
467/598
sulfhydryl AAs
DMF-phosphate buffer (1:1, v/v), pH 7.0
–
89
60
467/–
sulfhydryl AAs
DMF-phosphate buffer (1:1, v/v), pH 7.0
–
89
61
408/504,533
Cys
CH3CN/Tris (1:1, v/v) with 5% DMF, pH 7.2
–
90
365/560
–
–
–
92
365/510
Cys/Hcy
CH3CN/H2O (4:1, v/v), pH 7.2
–
92
360/615
Hcy
DMSO/HEPES buffer (9:1, v/v), pH 7.2
–
94
69
360/547,586
Cys/Hcy
DMSO/HEPES buffer (9:1, v/v), pH 7.2
–
95
70
–/572
Cys/Hcy
HEPES buffer, pH 7.2
–
96
71
365/545
Cys/Hcy
PBS buffer, pH 7.4
–
97
72
360/590
Cys/Hcy
CH3CN/PBS buffer (3:1, v/v), pH 8.1
–/0.13 mM
98
74
323/606
Hcy+Cys/Trp
CH3CN/HEPES buffer (1:1, v/v), pH 7.4
–
100
75
358/587
thiol AAs
DMF/HEPES buffer (4:1, v/v), pH 7.2
–
101
63 68
cr
us
an M
ed
ce pt
Ac
62
ip t
35-Cu2+
Page 180 of 184
–/603
Cys/Hcy
CH3CN/H2O (4:1, v/v), pH 7.2 (living cells)
– (–)
102
80
430/564
Hcy/Cys/Trp
CH3CN/HEPES buffer (1:1, v/v), pH 7.5
36.9/67.6/24 nM
31
81
467/595
sulfhydryl AAs
DMF/H2O (1:1, v/v), pH 7.4
–
105
82
455/598
thiols
CH3CN/H2O (4:1, v/v), pH 7.4
–
106
84
456/612
Cys/GSH
HEPES buffer, pH 7.0
20.1/19.8 nM
107
86
460/720
Cys/Hcy
DMSO/HEPES buffer (9:1, v/v)
1.41/1.19 μM
108
87
450/605
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
0.5/0.4 μM
109
88
450/607
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
0.4/0.2 μM
109
89
450/612
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
0.2/0.5 μM
109
90
482/622
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
1.0/0.3 μM
109
91
439/605
Cys /Hcy/GSH
HEPES buffer, pH 7.5
229/227/242 nM
110
92-Cu2+
479/514
Cys /Hcy/GSH
PBS buffer with 1% DMSO, pH 7.4
–/–/10 nM
111
94-Cu2+
485/515
Cys/Hcy/GSH
HEPES buffer with 1% CH3CN, pH 7.4
9 μM/–/–
112
96-Cu2+
335/453
α-AAs (His)
EtOH/H2O
– (2.1 ppm)
113
97-Cu2+
431/~505
α-AAs (Gly)
EtOH/H2O
– (2.0 ppm)
114
98-Cu2+
355/~405
α-AAs
EtOH/H2O
–
115
99-Cu2+
410/460,485
α-AAs (Gly)
THF
–(7.7 nM)
117
100-Cu2+
367/429
Cys
THF
0.5 μM
118
100-Ni2+
367/429
His/Trp
THF
–
118
101-Cu2+
310/410
–
–
–
119
102-Cu2+
310/410
–
–
–
119
103-Cu2+
400/528
Cys/GSH
aqueous solution
45/40 nM
120
104-Cu2+
320/481
His
DMSO/H2O
–
121
DNA-1/105/Cu2+
490/540
His
Tris-HCl buffer, pH 7.0/diluted urine
10 nM/–
122
DNA-1/105/Hg2+
490/540
Cys
Tris-HCl buffer, pH 7.0
5.1 nM
122
DNA-2/106/Cu2+
360/575
His
Tris-HCl buffer, pH 7.0
1 μM
123
cr
us
an M
ed
ce pt
Ac
ip t
77
DNA-3/107/Cu2+
399/608
His
HEPES buffer, pH 7.0
3 nM
124
Tb3+/DNA-4/Hg2+
290/546
Cys/Hcy/GSH
Tris-HAc buffer, pH 7.9
0.5 μM/–/–
125
DNA-5/108/Hg2+
360/583
Cys/GSH
Tris-HCl buffer, pH 7.0
5 nM/–
126
DNA-6/109/110
480/518
Cys/GSH
MOPS buffer, pH 7.45
4.2/4.1 nM
127
111/DNA-7/Hg2+
440/485
Cys/GSH
Tris-HCl buffer, pH 7.2
8.4/13.9 nM
128
GO/112/DNA-8
455/605
Cys/GSH
Tris-HCl buffer, pH 7.0
6.20/4.60 nM
129
113−Hg2+−T
350/420,630
Cys
PBS buffer, pH 7.4
60 μM
130
114-Ag+
333/456
Cys
dioxane
90 nM
131
115-Ag+
333/416,560
Cys
dioxane
150 nM
131
Page 181 of 184
480/538.2
Cys
HEPES buffer, pH 7.0
44 nM
132
GO/DNA-11/Ag+
493/520
Cys
HEPES buffer, pH 7.4/human serum
–/5 nM
133
GO/DNA-12/Ag+
480/520
Cys
Tris-HCl buffer, pH 8.0/human urine
0.1 μM/–
134
Tb3+/DNA/Ag+
290/546
Cys
Tris-HAc buffer, pH 7.9
–
135
116–Co2+
352/416
Cys
PBS buffer, pH 7.4
0.16 μM
136
117
365/567
Cys/Hcy
HEPES buffer, pH 7.2 (living cell)
2.4/1.2 mM (–/–)
32
118
–/564
Cys/Hcy
PBS buffer, pH 7.0
–
138
119-ZIF-90
–/~430
Cys/H2S
–
25 μM/–
139
Ac
ce pt
ed
M
an
us
cr
ip t
GO/DNA 9,10/Ag+
Page 182 of 184
Table(s)
Table 2. Summary of fluorescent/luminescent amino acid sensors based on hybrid organic-metal nanoparticles/nanoclusters Particle size
λex/λem (nm)
Specificity
Condition
Detection limit
Ref.
CdSe/ZnS QDs
3.1 nm
388/565
L-Cys
phosphate buffer, pH 7.8
3.8 nM
150
CdS QDs
4–6 nm
370/540
Cys
PBS buffer, pH 9
5.4 nM
151
120/Au NPs
24 nm
680/747
Cys/Hcy/GSH
PBS buffer, pH 7.4
BSA-Au NCs-Ni2+
1 nm
480/605
His
121/Ag NPs/C NPs
~100 nm
–/~515
Hcy–CdTe QDs
2.93 nm
CuInS2 QDs
ip t
NPs/NCs
157
Tris-HCl buffer, pH 7.0
30 nM
158
Cys/GSH etc.
sodium acetate buffer, pH 5.0
0.2 μM/20 nM
159
360/574
His
Tris-HCl buffer, pH 9.0
0.3 μM
160
–
–/660
Cys/GSH/His/Thr
PBS buffer, pH 7.0
0.5/–/0.7/2.0 μM
163
DA–CdTe QDs
2 nm
400/568
L-His
Tris-HCl buffer, pH 8.6
0.5 μM
164
CdTe/CdS QDs
2 nm
370/545
Cys/Hcy
Tris-HCl buffer, pH 7.4
0.78/0.67 μM
165
QDs–TiO2
–
–/580
Cys/Hcy/GSH
citrate buffer, pH 6.0
–/–/0.17 μM
166
DNA-14/Ag NCs
–
550/610
Cys/Hcy/GSH
PBS buffer, pH 7.4
4 nM/0.2 μM/4 nM
169
DNA-15/Ag NCs
–
–/615
Cys/Hcy/GSH
–
2.1/1.5/6.2 nM
170
DNA-CuNCs
–
340/580
Cys/Hcy/GSH
MOPS buffer, pH 7.5
2/5/2 mM
171
122-Au NPs
5.1±0.8 nm
370/420,450,475
Cys
aqueous solution
25 nM
177
123-Au NPs
13.8±1.5 nm
–/514
Asp/Glu
Pure water
32/57 nM
178
BSA-Au NCs
1 nm
360/660
Cys/Hcy/GSH
MOPS buffer, pH 7
8.3/14.9/9.4 nM
179
124-Ag NCs
–
510/615
Cys
PBS buffer, pH 7.0
20 nM
180
125-Ag NCs
2 nm
375/455
Cys/Hcy/GSH
boric acid–borax buffer, pH 8.2
42/47/380 nM
183
HSA-Au/Ag NCs
1.5±0.2 nm
510/620
Cys+HCy
PBS buffer, pH 7.0
15 nM
184
Ac
ce pt
ed
M
an
us
cr
10 nM/–/–
Page 183 of 184
Table(s)
Table 3. Summary of chiral recognition of AAs using fluorescent/luminescent sensors λex/λem (nm)
Specificity
KD/KL
FD/FL
Condition
Detection limit
Ref.
Cu-(S)-126
–/–
Pro/Phe/Trp
–/–/–
3.89/0.33/0.63
tetraborate buffer, pH=7.3
–/–/–
217
L-126
344/516
Pro/Val
–/–
2.778/0.618
borate buffer, pH=7.0
–/–
219
L-128
346/515
Pro/Val
–/–
1.757/0.563
borate buffer, pH=7.0
–/–
219
L-129
341/514
Pro/Val
–/–
1.782/0.488
borate buffer, pH=7.0
–/–
219
L-130
341/516
Pro/Val
–/–
3.788/0.585
borate buffer, pH=7.0
–/–
219
131-Cu+
230/359
Leu/Pro
–/–
–/–
EtOH
–/–
221
L-QDs-GNRs
400/720
Cys
–
2.57
Tris-HCl buffer, pH 6.6
0.8 nM
222
D-QDs-GNRs
400/720
Cys
–
–
Tris-HCl buffer, pH 6.6
0.8 nM
222
L-GSH–Ag NCs
350/440
L-Cys
–
–
PBS buffer, pH=7.4
3.4 nM
223
132-Cu2+
331/380
Phe/Ala/Val/Pro
–/–/–/–
–/–/–/–
MeOH/HEPES (1/1, v/v), pH=7.4
–/–/–/–
224
133-βCD-Au NP
440/520
Trp/Phe/Tyr
61.3/37/29.3
–/–/–
Tris-HCl buffer, pH 7.6
0.59/1.2/1.5 μM
226
Ac
ce pt
ed
M
an
us
cr
ip t
Complex or NPs
Page 184 of 184
S0010-8545(15)00177-0 http://dx.doi.org/doi:10.1016/j.ccr.2015.05.008 CCR 112079
To appear in:
Coordination Chemistry Reviews
Received date: Revised date: Accepted date:
25-1-2015 4-4-2015 11-5-2015
Please cite this article as: J. Wang, H.-B. Liu, Z. Tong, C.-S. Ha, Fluorescent/Luminescent Detection of Natural Amino Acids by Organometallic Systems, Coordination Chemistry Reviews (2015), http://dx.doi.org/10.1016/j.ccr.2015.05.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Edited May 11
Fluorescent/Luminescent Detection of Natural Amino
ip t
Acids by Organometallic Systems
School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi 530004,
us
a
cr
Jing Wang,a Hai-Bo Liua*[email protected], Zhangfa Tonga, Chang-Sik Hab*[email protected]
People's Republic of China
an
Department of Polymer Science and Engineering, Pusan National University, Busan 609-735, Korea
M
b
Highlights
te
luminescent organometallic systems
d
A wide variety of approaches in designing amino acid (AA) sensors based on fluorescent and
Ac ce p
Sensing mechanisms employed by organometallic systems for fluorescent and luminescent AA sensing Different roles of metals and organic parts played in selective AA sensing Chiral recognition to discriminate AA enantiomers (i.e., D and L) Pattern recognition to distinguish a range of AAs simultaneously
ABSTRACT
In comparison with other detection technologies, fluorescence/luminescence technology has become a powerful tool owing to its advantageous features including simplicity, low cost, high sensitivity, quick response time, easy sample preparation, noninvasive and nondestructive nature, etc. Due to the 1 Page 1 of 184
Edited May 11
important roles played by 20 natural amino acids in living systems, this review focuses on recent contributions
(from
the
year
2000
until
July
2014)
regarding
the
development
of
fluorescent/luminescent chemosensors and chemodosimeters to detect specific AAs, as well as chiral recognition to discriminate AA enantiomers (i.e., D and L), and pattern recognition to distinguish a
ip t
range of AAs simultaneously based on fluorescent/luminescent organometallic systems, which include
cr
organic–metal complexes and hybrid organic–metal nanoparticles/nanoclusters.
an
and chemodosimeters; chiral recognition; pattern recognition
CONTENTS
4
M
ABBREVIATIONS ABSTRACT
6 6
d
1. Introduction
7
te
2. Detection Mechanisms
us
Keywords: Amino acids; fluorescent and luminescent detection; organometallic systems; chemosensors
Ac ce p
2.1. Binding Site-Signaling Subunit Approach
7
2.2. Displacement Approach
8
2.3. Chemodosimeter Approach
8
3. The Advantages of Metal and Organic Combination 4. Organic-Metal Complexes
4.1. Small Molecule-Metal Complexes 4.1.1. Using Binding Site-Signaling Subunit Approach
9 10 10 10
4.1.1.1. Zinc Complexes
10
4.1.1.2. Copper Complexes
12
4.1.1.3. Iridium Complexes
13
2 Page 2 of 184
Edited May 11
4.1.1.4. Others
14 16
4.1.2.1. Zinc Complexes
16
4.1.2.2. Copper Complexes
17
4.1.2.3. Silver Complexes
21
ip t
4.1.2. Using Displacement Approach
4.1.2.4. Mercury Complexes
4.1.2.5. Others
24 25
an
4.1.3. Using Chemodosimeter Approach
25 26
M
4.1.3.1. Platinum Complexes
4.1.3.3. Ruthenium Complexes
23
us
4.1.2.4.2. Chemosensing of other AAs
4.1.3.2. Iridium Complexes
21
cr
4.1.2.4.1. Chemosensing of Cys
21
28
31
te
4.2. Polymer-Metal Complexes
30
d
4.1.3.4. Copper Complexes
Ac ce p
4.2.1. Using Displacement Approach 4.2.1.1. Copper Complexes
31 31
4.2.1.1.1. Introducing Cu2+ binding sites into the polymer side chains
31
4.2.1.1.2. Using the ensembling strategy of DNA and Cu2+
4.2.1.2. Mercury Complexes
33 34
4.2.1.2.1. Using the ensembling strategy of DNA and Hg2+
34
4.2.1.2.2. Using the formation and dissociation strategy of polymer-Hg2+ complex 36 4.2.1.3. Silver Complexes 4.2.1.3.1. Introducing Ag+ binding sites into the polymer backbone
36 36
3 Page 3 of 184
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4.2.1.3.2. Using the ensembling strategy of DNA and Ag+
37
4.2.1.4. Cobalt Complexes
38
4.2.1.4.1. Introducing Co2+ binding sites into the polymer side chains
38
4.2.2. Using Chemodosimeter Approach
38 38
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4.2.2.1. Iridium Complexes 4.2.2.2. Metal-Organic Frameworks (MOF)
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5. Hybrid Organic-Metal Nanoparticles/Nanoclusters
39
40
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5.1. Small Molecule-Functionalized Metal Nanoparticles/Nanoclusters 40
5.1.2. Using Displacement Approach
40 41
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5.1.1.1. Gold Nanoparticles 5.1.1.2. Quantum Dots
40
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5.1.1. Using Binding Site-Signaling Subunit Approach
42 42
5.1.2.2. Silver Nanoparticles
43
5.1.2.3. Quantum Dots
43
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5.1.2.1. Gold Nanoparticles/Nanoclusters
5.2. Polymer-Functionalized Metal Nanoparticles/Nanoclusters
45
5.2.1. Using Binding Site-Signaling Subunit Approach
45
5.2.1.1. DNA-Templated Silver Nanoclusters
45
5.2.1.2. DNA-Templated Copper NanoClusters
46
5.2.2. Using Displacement Approach
47
5.2.2.1. Polymer-Templated Gold Nanoparticles/Nanoclusters
47
5.2.2.2. Polymer-Templated Silver Nanoclusters
48
6. Chiral/Enantiomeric Recognition 6.1. Using Binding Site-Signaling Subunit Approach
49 50
4 Page 4 of 184
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6.1.1. Introducing Chirality into the Binding Site of the Sensor 6.1.1.1.
Introducing
Chirality
into
50 Dansylated
Cyclodextrins
50 52
6.1.1.3. Introducing Chirality into Quantum Dots
52
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6.1.1.2. Introducing Chiral Molecules as Binding Sites
6.2. Using Enantioselective Indicator Displacement Assays
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7. Pattern Recognition 8. Conclusions
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Acknowledgment References
GSH
53 53 54 57 58 59 70
d te
amino acids
Hcy
homocysteine
glutathione
ET
electron transfer
NPs
nanoparticles
NCs
Tpy
terpyridine
Phen
Trp
tryptophan
Phe
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AAs
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Figure Captions
ABBREVIATIONS
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6.1.2. Labeling Amino Acids Enantiomers with the Fluorescence Indicator
nanoclusters 1, 10-Phenanthroline phenylalanine
His
histidine
Val
valine
Ala
alanine
Pro
proline
Asp
aspartic acid
Glu
glutamic acid
Cys
cysteine
Arg
arginine
ICT
intramolecular charge-transfer
LOD
limit of detection
5 Page 5 of 184
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THF
tetrahydrofuran
LMCT
PBS
phosphate-buffered saline
DMF
PET
photoinduced electron transfer
BINOL
metal-to-ligand charge transfer
dimethylformamide
IFE
DMSO dimethyl sulfoxide
1,1′-bi-naphthol
fluorescence inner filter effect
T
thymine
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MLCT
ligand-to-metal charge transfer
reduced graphene oxide
pba
4-(2-pyridyl)benzaldehyde
acac
acetylacetone
bpy
2, 2’-bipyridine,
FRET
fluorescence resonance energy transfer
Ser
serine
PL
photoluminescence
ECL
DNBS
2, 4-dinitrobenzenesulfonyl
G
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rGO
NIR
near infrared
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d
quantum dots bovine serum albumin
IDA
indicator-displacement assay
MeOH
human serum albumin
dopamine
Leu
leucine
Asn
asparagine
methionine
Ile
isoleucine
glycine
Lys
lysine
Gln
glutamine
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Gly
HSA
mercaptoacetic acid
DA
gold nanorods
Met
MAA
threonine
mercapto propionic acid
GNRs
sodium citrate
Thr
tyrosine
MPA
HEPES
te
BSA
Tyr
N-ethylmaleimide
dsDNA double-stranded DNA
cytosine
QDs
guanine
NEM
ssDNA single-stranded DNA C
electrochemiluminescence
methanol
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
6 Page 6 of 184
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1. INTRODUCTION
Amino acids (AAs) are important components in a range of chemical and biological systems. They combine to yield proteins, enzymes, structural elements and many other molecules with biological
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activity. Their role as building blocks in living systems, along with the discovery that the concentration of free AAs is closely related to the metabolism of peptides and proteins in life and various
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physiological processes, has prompted increasing interest in their detection in various fields, such as
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chemistry, biochemistry and clinical chemistry [1-4]. In view of the role played by the 20 natural AAs in daily life [5-17], the development of techniques for sensing and monitoring natural AAs is important
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in the diagnosis and treatment of diseases.
Among the different methods applied to the detection of AAs, fluorescence/luminescence
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spectroscopic techniques, have drawn substantial interest from researchers owing to their advantageous features including simplicity, low cost, high sensitivity, quick response time, easy sample preparation,
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noninvasive and nondestructive nature, real-time analysis, and diverse signal output modes. Natural
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AAs exhibit similar properties because of the special arrangement of their carboxyl and amino groups.
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The key requirement of fluorescent/luminescent approaches to selective and discriminative detection of target AAs are fluorescent/luminescent probes that have the ability to differentially interact with the target AAs in a manner that gives rise to different optical signal outputs. Chemosensors that rely on the coordination are not as selective as preferred because of their relatively low selectivity and the structural similarity of natural AAs [18]. Therefore, the achievement of a selective AA recognition represents a challenge [19-21], a combination of stronger binding sites in a recognition system is an important factor in designing effective AA receptors. However, selective detection of a specific AA without interference from other AAs is difficult. As far as selectivity is concerned, chemodosimeters provide an ideal way to design fluorescent/luminescent probes, in which a significant chemical transformation involving the breaking or formation of several covalent bonds was induced by a specific natural AA. Currently, 7 Page 7 of 184
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organic-metal based fluorescent/luminescent probes are extensively used as one of the most successful strategies [22] for detecting AAs, which however have not been systematically summarized to our knowledge. Although studies on the use of chemosensors for the detection of AAs have been reviewed by Zhou
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and Yoon [21], a large number of important studies on natural AA sensing based on organometallic systems were not discussed in their review. Therefore, we focus particular attention to review the
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literature from 2000 to July 2014, covering the fluorescent/luminescent probing of 20 natural AAs by
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organometallic systems. Other AAs such as homocysteine (Hcy) and glutathione (GSH), as well as derivatives of AAs, were not included in this review. This review provides a reference for those who are
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interested in this growing and exciting research field.
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2. Detection Mechanisms
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2.1. Binding Site-Signaling Subunit Approach
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In the binding site-signaling subunits approach [23-25], the ‘‘binding site” part (receptor) and
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“signaling subunit’’ part (indicator) are linked through a covalent bond, and the interaction of the analytes (such as AAs) with the binding site alters the electronic properties of the signaling subunit, resulting in sensing of the target analytes via color, absorption or emission modulation. The binding between the receptor and analyte is typically labile and reversible, and involves different interactions, including electronic interactions, hydrogen bonding and metal-ligand interactions, etc.
2.2. Displacement Approach
The displacement approach [26] uses binding sites and signaling subunits to form a molecular ensemble through non-covalent interactions. Upon the addition of a specific amino acid (AA), the 8 Page 8 of 184
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indicators are replaced, resulting in a change in their optical properties. This type of supramolecular approach toward sensing is very simple to implement. Furthermore, the sensitivity and selectivity of the assay can be modulated by varying the receptor-indicator ratio or sensing conditions (e.g. pH).
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2.3. Chemodosimeter Approach
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Chemodosimeters [27] are molecular devices that interact with their analytes and yield physically
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measurable signals in an irreversible manner. Conventional chemodosimeters are generally molecular assemblies of receptor and signaling units. In contrast to chemosensors, which respond to the real-time
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concentration of their analytes, chemodosimeters respond to their analytes in a cumulative manner. Compared with chemosensors, chemodosimeters have advantages in terms of selectivity and sensitivity,
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and their cumulative effect plays an important role in the detection of analytes [28].
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3. The Advantages of Metal and Organic Combination
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For detecting AAs, metal ions can play an important role [29]: (1) they can represent the active site for interacting with AAs [30]. They serve as binding sites in the development of AA probes. An obvious requirement for an organic-metal combined system to serve as a binding site is its stability. (2) The interaction between a metal centre and AAs is often a convenient route for achieving strong binding [26]. In this case, AAs can capture metals from organometallic systems and the organic part can be displaced by the AAs. (3) Metal ions can also be used profitably as structural elements for assisting AAs binding without exerting any a direct interaction with AAs [31-32]. Organic-metal complexes have widespread use in molecular recognition [33-34]. Metal ions are positively charged in aqueous solutions but the charge can be manipulated depending on the coordination environment so that a metal complexed by ligands (organic part) can be cationic, anionic 9 Page 9 of 184
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or neutral. Metal complexes have advantageous photophysical properties, such as high stability and relatively long lifetimes compared with those of organic fluorophores. The ligands impart their own functionality and can tune the properties of the overall complex to make it unique compared with those of the individual ligand (organic part) or metal. In addition, metal complexes can be modified easily
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with different functional groups to tune the energy band. The application of metal nanoparticles (NPs) [35-37] in bioanalysis has attracted considerable
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interest because of their remarkable optical, electrical and chemical properties. In particular, ligand-
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protected metal NPs are being explored increasingly as analytical tools in many biological fields. The introduction of organic ligands onto NP surfaces not only provides stability, but also desirable surface
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functionalities. In addition, the recently developed semiconductor quantum dots show great promise as fluorescence probes owing to their improved photophysical properties, including high quantum yield,
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size-tunable narrow emissions and minimal photobleaching compared with conventional organic fluorophores. Because surface-bound electron-rich small organic molecules can transfer electrons
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efficiently to quantum dots, the successful application of this fundamental electron transfer (ET) process
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has been the analysis of a wide range of analytes.
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Combinations of organic functions and metal ions can have advantages, such as tunable, welldefined coordination geometries, and interesting photophysical properties, such as long emission lifetimes (100 ns to ms), tunable emission wavelengths, high photostability and large Stokes shifts (hundreds of nm), as well as alternative binding interactions and pathways.
4. Organic-Metal Complexes
In the process of the design of fluorescent/luminescent probes, based on organic-metal complexes, proper constitutional components, such as fluorophores, metals and binding units must be chosen to construst the target AA chemosensors/chemodosimeters. With different metal coordination sites and 10 Page 10 of 184
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fluorophores fitted onto the organic-metal complexes, varied interactions or binding modes occur. For example, the fluorescent ligands, such as terpyridine (Tpy), 1, 10-Phenanthroline (Phen), and nonfluorescent ligands, such as crown ethers, calixarenes, bipyridine, etc. are frequently used as metal coordination sites; the fluorophores, such as pyrene, dansyl, rhodamine, etc. are commonly used as the
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signaling reporters. In the following sections, we will indicate the designing rules that have been applied in the practical examples for gaining metal-organic combinational fluorescent/luminescent
4.1. Small Molecule-Metal Complexes
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4.1.1. Using Binding Site-Signaling Subunit Approach
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chemosensors or chemodosimeters.
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In this approach, the metal ion center had been developed as binding sites of AAs due to the
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4.1.1.1. Zinc Complexes
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metal center and AAs.
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covalent or noncovalent interactions, such as electronic and hydrogen interactions, etc. between the
The zinc ion center have been used as the binding sites due to the electronic interaction between Zn2+ and AAs. In 2001, Fabbrizzi et al. reported a zinc complex of tetramine 1 with anthracene as signaling reporter for the sensing of AAs (Figure 1) [38]. Although only tryptophan (Trp) induced fluorescence quenching of [Zn(1)]2+ due to Zn2+-carboxylate coordinative interaction as well as ET process from indole (donor) to anthracene fragment (acceptor), among all the natural AAs examined, the presence of phenylalanine (Phe) interfered with the sensitivity of the complex [Zn(1)]2+ toward Trp. Zhang et al. applied complex 2 (Figure 1) to signal histidine (His) in methanol (MeOH)/H2O cosolvents as well as in aqueous solution using the optode membrane [39]. The zinc centre acted as an 11 Page 11 of 184
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acceptor, whereas the transduction signal for the recognition process was realized through the pyrene excimer fluorescence. Although 2 could interact with other AAs and anions, the large difference in the fluorescence response of 2 to AAs and anions means that this sensor meets the selectivity requirements of a His assay in physiological fields.
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Nag et al. reported that the zwitterionic form of alanine (Ala), His, valine (Val) and proline (Pro), RN+H2…CO2-, were quite effective in binding with the [Zn2(3)]2+ fluorophore (Figure 2) [40] through
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their carboxylate unit with equilibrium constant values of 2.5(3)×105 for Ala, 3.1(2)×105 for His,
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4.4(4)×105 for Val and 8.0(5)×105 for Pro.
The compound 4 showed stronger fluorescence emission, as compared with 5 that lacks triazol part
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(Figure 2) [41]. The Zn2+ complex of 4, [Zn(4)(H2O)3]2+, interacted with L-aspartic acid (Asp) and Lglutamic acid (Glu) due to the coordination of the AAs to the Zn2+ ion, resulting in an increase in
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fluorescence emission with a hypsochromic shift. The binding constants calculated for the AAs were as follows; Ka (L-Asp)=1×104 M-1, Ka (L-Glu)=5.5×103 M-1. However, that study did not provide
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information on the selectivity of the 4-Zn2+ complex toward AAs.
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Recently, a modular approach was developed for fluorescence sensing of AAs to improve water
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solubility of receptors and their binding interactions to free AAs, in which Zn2+ complexes of Tpy derivatives and crown ethers are used as modules for coordination with carboxylates or Lewis basic side chains and π-containing side chains or Lewis acidic groups, respectively. The ammonium group of the zwitterionic AAs can coordinate with [Zn(6)]2+ because of the crown ether subunit in complex [Zn(6)]2+, thus providing a stronger binding affinity toward L-AAs, such as L-aspartate (K = 4.5×104 M−1) and Lcysteine (Cys) (K = 2.5×104 M−1), as compared with [Zn(7)]2+ without crown ether. The binding affinity of [Zn(6)]2+ with L-AAs is highly associated with the coordinating abilities of the side chain on AAs (Figure 2) [42]. On the other hand, it is difficult to differentiate L-aspartate from L-Cys. In addition, the interference of other AAs on the sensitivity of the receptor to a specific AA was not examined. Zn(8) (Figure 3) senses arginine (Arg) by blocking intramolecular charge transfer (ICT) from the crown ether 12 Page 12 of 184
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moiety to the Tpy-Zn2+ moiety, with an association constant Kass of 1.78×104 M−1 by forming a 1:1 complex [43]. By comparison, Zn(9) without the crown ether moiety and compound 9 exhibited negligible response upon the addition of Arg, showing that the crown ether moiety and Tpy-Zn2+ complex moiety in the receptor Zn(8) play important roles in Arg recognition. The Zn2+ complex of 10
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(Figure 4) can distinguish His from Cys, as well as other AAs [44]. In addition, 10-Zn2+ can also distinguish His from other imidazole derivatives. When treated with various AAs, the fluorescence
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enhancement of 10-Zn2+ solution (2.0×10−5 M/5.0×10−5 M) was observed only in the presence of His,
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accompanied by the formation of a white milky precipitate, which was a polymer formed through the interaction of the entire His molecule with the complex 10-Zn2+. The precipitate exhibits stronger
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fluorescence than the soluble components, which can be attributed to the significantly increased structural rigidity of the solid-state polymeric structures. By comparison, 11-Zn2+ and 12-Zn2+ showed
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4.1.1.2. Copper Complexes
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Insert Table 1 and Figures 1-4 Herein
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no fluorescence response to His and other AAs.
Following the binding site-signaling subunit approach, copper complexes have been successfully applied in detecting His, in which His acted as an additional ligand through coordinating to the copper ion center. For instance, complex 13 (Figure 5), which consists of Tpy and CuCl2, was used for L-His detection [45]. L-His was coordinated with a more basic imidazole nitrogen (vs. the carbonyl group) and an α-amine group to the Cu2+ center of complex 13 by forming a 1:1 complex between 13 and L-His, with an association constant of 8.94×103 M−1. Upon coordination of L-His with 13, the Cu2+ center became more electron-rich, which makes the electron or energy transfer from the excited state of Tpy more difficult, resulting in significant fluorescence enhancement of Tpy. 13 Page 13 of 184
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The Cu2+ complex of 14, (Cu2+)2(14) [46], showed selective detection of His and Cys through different recognition pathways (Figure 6). When Cys or His is added to (Cu2+)2(14), the fluorescence emission increased linearly in the range of 90 mM to 2,800 mM for Cys and 200 mM to 3,200 mM for His. In the presence of excess Cys and His, Cu2+ was removed from the (Cu2+)2(14) and (Cu2+-His)2(14)
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was formed, respectively. The binding constant between (Cu2+)2(14) and His was (1.4±0.03)×104 M−2. (Cu2+)2(14) was used for the quantitative estimation of total [Cys]+[His] present in human blood plasma.
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Qian et al. reported that the Cu2+ complex of 15 (Figure 6) could discriminate His from other α-AAs
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with high selectivity and sensitivity [47]. Upon addition of His (0 µM to 80 µM), the fluorescence of 15 at 537 nm that was quenched by Cu2+ was recovered, along with the enhancement of fluorescence
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intensity at 476 nm. In this process, His acted as a chelating ligand binding to Cu2+, which changed the mode of Cu2+ that was coordinated with the pyridine N atom of 15 and reduced the charge density in the
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Cu2+ ion, resulting in the enhanced ICT effect and blockage of the ligand-to-metal charge transfer
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Insert Figures 4-6 Herein
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(LMCT).
4.1.1.3. Iridium Complexes
In the sensing of AAs based on iridium complex, the iridium iron center acted as binding sites through covalent interactions between iridium and AAs. As observed by Wong et al. [48], the iridium complex [Ir(16)]+ (Figure 7) showed enhanced fluorescence upon coordination with His through covalent attachment with the imidazole moiety of His via a ligand substitution reaction with the H2O ligand. The fluorescence intensity of [Ir(16)]+ (50 μM) showed up to 180-fold enhancement at a ratio of [His]/[Ir(16)]+ ≥ 4:1 without interference from other natural AAs. Chen and coworkers used iridium complex 17 (Figure 8) for the time-dependent detection of Cys 14 Page 14 of 184
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[49]. Upon addition of Cys within 30 min, DMF and Cl on 17 are rapidly displaced with 2 mol of thiolates by forming complex 18, with an evident emissive color change from green to orange. After 30 min, complex 19 was formed, with an emissive color change from orange to green, through the intramolecular cyclization reaction to form a six-membered ring via replacement of one of the thiolates
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by the amino group.
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Insert Figures 7-8 Herein
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4.1.1.4. Others
Gold Complexes: Tae et al. reported a rhodamine-based gold complex 20-Au+ (Figure 9) that
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exhibited colorimetric and fluorescent turn-on selectivity and sensitivity toward Cys compared with the other AAs examined through color changes from colorless to red and changes in emission spectra [50].
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Binding of the thiol group of Cys to complex 20-Au+ increases the acidity of the thiol proton. The
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proton released subsequently stabilizes the open form of the rhodamine probe to obtain complex 21.
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Simple thiols, such as propanethiol, cannot induce changes in the fluorescence intensity of 20-Au+. Cerium Complexes: The selective recognition of Trp by metal–organic tetrahedral Ce(22) [51] was reported by Duan and Jia et al. (Figure 10). When Trp was added to Ce(22), the luminescent emission was enhanced, leading to the association between Ce(22) and Trp in 1:1 stoichiometry, with an association constant (logKass) of 3.14±0.27. Given the synergistic effects of hydrogen bonding, πstacking, and size/shape matching, 0 mM to 0.1 mM of Trp can be detected quantitatively. Ce(22) can be used to detect Trp in living systems and serum samples. By contrast, peptides containing Trp residues [52] were not detected range with the use of Ce(22) because of size restriction. Aluminum Complexes: Lodeiro and Oliveira et al. detected a turn-on selective fluorescent probe, aluminum complex of 23 (Figure 10), for His in HEPES buffer and in real urine samples [53]. The 15 Page 15 of 184
Edited May 11
fluorescence intensity of 23 (10 μM) was enhanced 10-fold by His (30 μM). By contrast, the addition of His (30 μM) to the system 23-Al3+ (10 μM) induced a stronger enhancement (100-fold) in the emission intensity. The association constants logKass were (1(23):1Al3+) = 5.63 ± 0.02, (1(23):2His) = 10.4 ± 0.01, and (1(23):1Al3+:2His) = 8.99 ± 0.02.
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Silver Complexes: Kumar and coworkers synthesized the thiacalix[4]arene-based fluorescent receptor 24 (Figure 11), which showed good selective binding ability to Ag+ and Fe3+. Ag+(24) and
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Fe3+(24) (illustrate in section 4.1.2.5.) complexes were then prepared for Cys detection [54]. Compound
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24 produced weak monomer and strong excimer emissions of the pyrene group at 377 and 470 nm, respectively, indicating that the two pyrene moieties on 24 are stacked together. Coordination of 24 with
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Ag+ produced a ratiometric response, in which I377/I470 increased. Quenching in excimer emission was attributed to conformational change via the interaction of Ag+ with nitrogen atoms of pyrene arms and
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sulfur atoms of the thiacalix[4]arene moiety of 24. Addition of Cys to the Ag+(24) complex induced a significant quenching in the monomer emission and a small revival of excimer emission, revealing that
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the Ag+(24)complex.
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the stacking of two pyrene moieties was prevented because Cys is unable to remove the Ag+ ion from
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Cobalt Complexes: Wang et al. constructed an optode membrane by immobilizing the sensing material, 25 (Figure 12), as a fluorescent reporter [55]. 25 consisted of meso-tetraphenylporphyrin cobalt(II), as a molecular probe, and the covalent attachment of meso-tetraphenylporphyrin. The low fluorescence emission of the porphyrin dimer at 657 nm was attributed to photoinduced electron transfer (PET) from the inner free-base porphyrin in the singlet excited state to a low-spin cobalt(II). The fluorescence enhancement of the membrane by His is based on the favorable extraction of His into the bulk organic membrane and the complexation with the inner metallopophyrin moiety as well as the inhibition of PET process. The optode membrane can be prepared easily and is selective to His over several AAs and common anions.
16 Page 16 of 184
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Insert Figures 9-12 Herein
4.1.2. Using Displacement Approach
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Chemosensing ensemble of metal–organic complexes is one of the most successful strategies for detecting AAs because it provides specific metal ion–AA interactions. In the displacement approach,
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AA competes for the metal ion in the complex of the conjugate during recognition events, thereby
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simply changing the metal ion or ligand of the ensemble.
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triggering a change in optical properties. Such a phenomenon can be used to detect AAs selectively by
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4.1.2.1. Zinc Complexes
In the search for molecular systems that provide selectivity, conjugates of calixarenes are
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noteworthy because these contain both a hydrophobic cavity and a hydrophilic rim, and can also provide
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an ideal platform for the development of receptors towards ions or molecular species depending upon
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their functionalization [22c]. Rao and coworkers have been active in developing calix[4]arene conjugates-metal chemosensors, and much impressive progress has been made recently (zinc complexes, silver complexes and cadmium complexes in sections 4.1.2.1, 4.1.2.3 and 4.1.2.5, respectively). Rao and coworkers reported a chemosensing ensemble of calix[4]arene conjugates 26–30 and Zn2+ ions for the selective detection of AAs (Figures 13-15). Among the naturally occurring AAs, Zn(26) (Figure 13) recognizes Asp, Cys, His, and Glu by exhibiting significant fluorescence quenching [56]. The ability of each AA to quench the fluorescence of Zn(26) showed the following trend: Asp > Cys >> Glu ≈ His, which was attributed to the protonation and chelating ability of the AAs as well as the π–π interaction ability of the side chain of the AAs with Zn(26). The fluorescence of Zn(27) (Figure 13) quenched by chelating with Cys and Asp was investigated among the 20 naturally occurring AAs [57]. 17 Page 17 of 184
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The fluorescence quenching observed in the presence of these AAs was attributed to the protonation of the Zn2+ coordination sphere, followed by the formation of a complex of Zn2+ with the AAs. Zn(28) (Figure 14) was utilized to probe Cys, in a fluorescence turn-off manner, which can be attributed to displacement of Zn2+ from Zn(28) by release of free 28 [58]. Zn(29) (Figure 15) could recognize His
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and Cys in HEPES buffer milieu and in HeLa cells. The successful sensing of His and Cys is due to the interaction of His and Cys with Zn2+, followed by the removal of Zn2+ from the coordination sphere
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[59]. Compound 30 (Figures 13) exhibited enhanced and blue shifted fluorescence from 535 nm to 495
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nm upon titration of Zn2+ by forming the Zn(30) complex. Zn(30) showed selectivity toward His, which may be ascribed mainly to the dechelation of Zn2+ from the coordination sphere of Zn(30), followed by
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formation of the His complex using its side chain imidazole [60].
1,1′-binaphthyl derivatives have been widely used as optical fluorophores due to their special C2
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axial chirality, rigid structure, relatively high emission efficience and readily selective functionalization [61]. Metal complexes with fluorophores of 1,1′-binaphthyl compounds, such as 1,1′-bi-naphthol
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(BINOL) etc. have been utilized for the recognition of AAs (zinc complexes of 31 in section 4.1.2.1,
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copper complexes of 41, 131 and 132 in sections 4.1.2.2, 6.1.1.2 and 6.2, respectively). In 2013, Li,
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Wang, and Yu et al. developed a Zn2+ complex of BINOL derivative 31 for probing His (Figure 13) via a displacement mode [62]. Upon titration of the 31-Zn2+ ensemble with His, the fluorescence intensity decreased, which could be attributed to dechelation of 31-Zn2+ and formation of the His-Zn2+ complex.
Insert Figures 13-15 Herein
4.1.2.2. Copper Complexes
Many AAs show strong binding ability to Cu2+, which indicates its ability as a powerful ligand over others in competitive complexation with Cu2+ [63]. Therefore, the AAs probe can be realized 18 Page 18 of 184
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conceptually using the “chemosensing ensemble” method, i.e. the design of a complex between Cu2+ and an indicator. This probe works simply by releasing the indicator from its copper complex by exchange with a special AA. In addition, the indicator forms a copper complex with a relatively weaker binding constant than the AA [64-65]. Following the “chemosensing ensemble” approach, several recent
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examples have been described according to the signaling fluorophores (indicator). Eosine Y fluorophore: Fabbrizzi et al. described the recognition of His using the [Cu2(32)]4+
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complex [66] as a receptor and eosine Y (33) as a fluorescent indicator (Figure 16). [Cu2(32)]4+
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quenched the fluorescence of 33 by forming a nonfluorescent [Cu2(32)]4+/33 1:1 ensemble with Kass = 107.2 M-1. The [Cu2(32)]4+/33 ensemble showed high selectivity toward His among the other AAs tested,
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which was attributed to the selective recognition of the ambidentate imidazole residue of His over the carboxylate group of natural AAs. His could displace the indicator of 33 from the receptor of
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[Cu2(32)]4+. 33 was released from the ensemble and the fluorescence was revived. Near-infrared (NIR) fluorophore: Zwitterionic dye 34 (Figure 17) showed NIR fluorescence
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emission [6]. After adding Cu2+ to the DMF solution of 34, the emission of 34 was quenched and a
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hypsochromic shifted from 875 to 850 was observed along with an immediate color change from blue to
Ac ce p
yellow. This was attributed to metal-to-ligand charge transfer (MLCT). The stoichiometry of the 34-Cu complex was confirmed to be 2 : 1 with a binding constant of 4.44×108 M-2. Upon exposure to Cys from 0 to 20 × 10-5 M, the blue-colored and NIR fluorescent 34 was released from its non-fluorescent copper complex (34-Cu), with a high-contrast colorimetric change from yellow to blue. 34-Cu could discriminate Cys selectively among the other analogs due to the cooperative effect of the thiol-aminocarboxylic acid moiety in Cys as a ligand to Cu2+ and the larger binding constant of Cys/Cu2+ (5.91×108 M-2) than that of 34/Cu2+ (4.44×108 M-2) and those of the other AAs with Cu2+. Dansyl fluorophore: Wu et al. developed a dual-functional probe for Cys and His based on the ensemble of 35 and Cu2+ (Figures 18) [67]. 35 responded to Cu2+ with fluorescence quenching and a binding constant of 3.98 × 106 M-1 in 1:1 stoichiometry. The fluorescence emission of 35 could be 19 Page 19 of 184
Edited May 11
released from complex Cu2+(35) upon the addition of His or Cys through different sensing process. The fluorescence recovery induced by His was attributed to the displacement mechanism, where His could capture Cu2+ from the Cu2+(35) complex, whereas the other AAs were faint because the stronger binding affinity between 35 and Cu2+ exceeded the binding between Cu2+ and most of the other AAs. The turn-
ip t
on detection of Cys was attributed to the reduction of a thiol group in Cys, which reduced the paramagnetic Cu2+ to diamagenetic Cu+. Therefore, the fluorescence of 35 quenched by Cu2+ was
cr
recovered.
us
Rhodamine fluorophore: Upon mixing with Cu2+ ions, the 36-Cu2+ complex (Figure 19) [68] was formed with a pink color and weak fluorescence, which might be due to the paramagnetic nature of Cu2+
an
ions (3 d9), and the fluorescence of the ring-opened amide form of 36 was quenched. When rhodamine B was introduced to a 36-Cu2+ complex solution, the fluorescence signal of rhodamine B was reduced
M
dramatically due to the overlap between emission spectra of rhodamine B and absorption spectra of 36Cu2+ through the fluorescence inner filter effect (IFE). The addition of Cys to the above solution
d
resulted in the preferential formation of a complex with Cu2+ compared with 36, resulting in the
te
dissociation of the 36-Cu2+ complex and a decrease in the fluorescence IFE of the solution. The
Ac ce p
fluorescence emission of rhodamine B was then measured. The displacement of the Cu2+ ion in the 36Cu2+ complex is not an exclusive feature of Cys, the present system can also show a similar response to other thiol-containing compounds, such as Hcy and GSH.68 Coumarin fluorophore: Yu and Li et al. used a Cu2+ complex of coumarin-based ligand 37 (Figure 20) as a selective turn-on fluorescent sensor for His from other naturally occurring AAs in aqueous solution and in biological fluids, such as human urine and fetal calf serum [69]. Compound 37 formed a nonfluorescent complex with Cu2+ in 1:1 binding mode, and the binding constant was 1.3×106 M−1. His was used to remove Cu2+ from the 37-Cu2+ complex because His with Cu2+ has a larger formation constant (log β1=10.16 and log β2=18.11) than that of 37 and Cu2+. The use of His resulted in ~80-fold enhancement of fluorescence at 500 nm upon addition of 120 equiv. relative to Cu2+. 20 Page 20 of 184
Edited May 11
Recently, Chan and Leung et al. also developed a coumarin-based ligand 38-Cu2+ complex (Figure 20) for the selective detection of His in a turn-on manner, which is applicable not only to aqueous solutions but also to living cells [70]. Upon adding His into the 38-Cu2+ ensemble, His is capable of removing Cu2+ from its ensemble by cooperative chelating action of the carboxyl and imidazole
ip t
moieties of His. The binding model of His-Cu2+ was 2:1, with an association constant of 2.54×109 M−2. Meanwhile, fluorescence recovery was also achieved by titrating the 38-Cu2+ ensemble with biothiols,
cr
Cys, Hcy, and GSH.
us
BODIPY fluorophore: Shao et al. prepared an ensemble of BODIPY-based derivative 39 and Cu2+, which was then used as a chemosensor for Cys and Hcy (Figure 21) [71]. Only Cys and Hcy induced
an
enhancement in fluorescence among the 20 natural AAs and Hcy because of the removal of Cu2+ from the 39·Cu2+ complex, resulting in fluorescence recovery of 39.
M
Quinazoline fluorophore: The quinazoline derivative 40-Cu2+ ensemble probe (Figures 21) was prepared by Chellappa et al. for the detection of Cys [72]. The addition of Cys induced decomplexation
d
of Cu2+ from the weakly fluorescent ensemble, resulting in restoration of the emission property of 40.
te
BINOL fluorophore: Feng et al. developed a BINOL (41)-based fluorescent thiol sensor (Figures
Ac ce p
22) [73]. Compound 41 showed an emission spectral band at 360 nm. This band was decreased upon the addition of Cu(NO3)2 and completely quenched with 1.0 equiv. Cu(NO3)2. In this process, 41 was oxidized to 42 and Cu(42) was formed. When Cys, Hcy, or GSH was added to Cu(42), the chelation of thiol-containing AAs with copper occurred, instead of the formation of Cu(42), thereby inducing fluorescence enhancement at 482 nm and green fluorescence under UV light, which corresponded with the fluorescence of 42. Recognition ability was in the following order: Cys/GSH > Hcy. Naphthalimide fluorophore: The ensemble of Cu2+ and naphthalimide-based ligand 43 (Figures 23) was designed as selective fluorescent thiol probe [74]. The fluorescence of the 43-Cu2+ ensemble was enhanced by thiols because of the replacement of Cu2+ from the ensemble by thiols and the release of fluorescent ligand 43. From the titration experiments, the association constants (logKass) were 4.02 for 21 Page 21 of 184
Edited May 11
Cys, 3.88 for Hcy, and 3.68 for GSH. In addition, the 43-Cu2+ ensemble showed high sensitivity and selectivity for fluorescence imaging of thiols in Chinese hamster ovary cells. Calix[4]arene derivative: The fluorescence of 30 (Figure 13) was completely quenched in the presence of Cu2+ [60]. 30-Cu2+ complex showed increased fluorescence intensity in the presence of Cys
ip t
among all the 20 AAs investigated, indicating the interaction of Cys with Cu2(30), followed by the
cr
dechelation of Cu2+ from the coordination sphere of this complex to form the Cys·Cu adduct.
us
Insert Figures 16-23 Herein
an
4.1.2.3. Silver Complexes
M
Rao et al. reported that the fluorescent receptors 44 and 45 for Ag+ can be used as a secondary recognition ensemble toward AAs. Calix[4]arene derivative 44 (Figure 24) [75] and Ag+ formed a 1:1
d
complex with an association constant (Ka) of 11117 ± 190 M-1. During the titration of 44-Ag+ with Cys,
te
Ag+ is being removed from the complex by Cys to release free 44 and the necessity of the -SH function
Ac ce p
on Cys was confirmed after removing the Ag+ from 44-Ag+ complex based on several analogous and control molecules. The 45-Ag+ ensemble (Figure 24) realized recognition toward Cys, Asp and Glu against 20 naturally occurring AAs [76], by switching-off the fluorescence of 45-Ag+. This was the reverse to what occurred when 45 was titrated with Ag+, indicating the removal of Ag+ by Cys and the release of free 45.
Insert Figure 24 Herein
4.1.2.4. Mercury Complexes 4.1.2.4.1. Chemosensing of Cys 22 Page 22 of 184
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In view of the strong affinity of Hg2+ towards thiols, the utility of the Hg2+ complexes for the detection of thiol based AAs, such as Cys, have receive highly interest from researchers. Wang et al. and Fu et al. proposed squarine-Hg2+ ensemble fluorescence assay for thiol containing AAs (Figure 25).
ip t
After binding with Hg2+, the fluorescence of 46 [77] and 47 [78] gradually extinguished due to the diminishment of the electron-donating ability of nitrogen atom that destroyed the donor–acceptor–
cr
donor (D–A–D) charge transfer upon the chelation of Hg2+ into the terminal binding units of 46 and 47.
us
Upon addition of thiol-containing AAs, the complex of 46-Hg2+ or 47-Hg2+ was dissociated, releasing free 46 or 47 from the ensemble owing to the stronger binding between thiols and Hg2+.
an
Correspondingly, 46-Hg2+ or 47-Hg2+ exhibited emission enhancement. The tunable measuring ranges of Cys can be achieved by varying the Hg2+ concentrations in the 47-Hg2+ ensemble.
M
Mahapatra et al. also used the ensemble strategy in designing a combination of carbazole derivative 48 (Figure 26) and Hg2+ to fabricate a turn-on fluorescent Cys probe [79]. Upon the addition of Hg2+, a
d
complex of 48-Hg2+ was formed, inducing a decrease in fluorescence as well as the solution color
te
change from nearly colorless to yellow. On increasing the concentration of Cys, the 48-Hg2+ complex
Ac ce p
decomposed to release 48 and the emission recovered. Compared with Cys, other mercapto biomolecules, such as Hcy and GSH, induced relatively slight increases in fluorescence. Singh et al. reported an Hg2+ complex of the crown ether–BODIPY ligand 49 that operates as an on–off fluorescence sensor for L-Cys over other AAs [80]. As shown in Figure 27, the recognition of Cys could be attributed to the release of 49 from the 49-Hg2+ complex (binding constant logβ=4.55), and the formation of the Cys-Hg2+ complex (binding constant logβ=6.33) resulted from the removal of Hg2+ by Cys. In addition, the Hg2+-doped hydrogel in the presence of 49 can be applied qualitatively to Cys sensing via gel–sol conversion and color changes from light orange to pink. Chellappa et al. developed an off–on fluorescent sensor based on the ensemble of quinazoline derivative 50 and Hg2+ (Figure 28) [81] that can be used to detect Cys. Addition of Cys caused 23 Page 23 of 184
Edited May 11
fluorescence restoration of 50, indicating the removal of Hg2+ from the ensemble. Jiang et al. and Lin et al. used an aggregation and deaggregation strategy in the design of perylene bisimide (PBI) derivatives 51 [82] and 52 [83] for detecting thiol-containing AAs (Figure 29). The fluorescence of 51 and 52 was quenched completely after adding Hg2+ by forming the nonfluorescent H-
ip t
aggregated Hg2+-51 ensemble and J-aggregated Hg2+-52 ensemble, respectively, via the thymine–Hg2+– thymine (T-Hg2+-T) binding mode. The quenched fluorescence of the Hg2+-51/52 ensemble was
cr
recovered upon the addition of thiol-containing AAs via deaggregation of the Hg2+-51/52 ensemble to
us
restore the PBI state 51/52.
Luo and Li et al. observed the response of the reduced graphene oxide (rGO)–organic dye 53-Hg2+
an
ensemble toward Cys (Figure 30) [84]. The fluorescence of 53 was quenched after titrating with rGO to form the rGO–53 complex because of long-range resonance energy transfer. In the presence of Hg2+,
M
highly selective adsorption of Hg2+ by rGO disrupted the interaction between 53 and rGO, thus restoring the fluorescence of 53. Upon adding Cys to the ensemble of rGO–53-Hg2+, Hg2+ was released from
d
rGO, which is attributed to the stronger binding of Hg2+ and Cys, resulting in reformation of the rGO–
Ac ce p
te
53 complex and fluorescence requenching of 53.
4.1.2.4.2. Chemosensing of other AAs
Very recently, a chemosensing ensemble of 54-Hg2+ toward L-pro was examined by Pal and Bag (Figure 31) [85]. The complex of 54-Hg2+ presented high selectivity toward L-pro among different AAs investigated in an absorption or fluorescence turn-off manner; a color change from pink to colorless was also observed. In 2012, our group designed a highly ordered mesoporous SBA-15 nanosensors 55 (Figure 31) that is capable of binding Hg2+ and detecting 20 natural α-AAs except for Trp, by a Hg2+-mediated approach [86]. After binding Hg2+, the fluorescence emission of 55 quenched due to the PET process from the 24 Page 24 of 184
Edited May 11
exited dansyl moiety to the proximate Hg2+, with Kass of 1.32 × 105 M-1 between 55 and Hg2+. The successful sensing of α-AAs has been realized by snatching Hg2+ from the 55–Hg2+ due to the larger stability constant of the complex formed by the α-AAs and Hg2+ compared with that of 55 and Hg2+, in
ip t
which the quenched fluorescence of 55 by Hg2+ was recovered.
cr
Insert Figure 25-31 Herein
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4.1.2.5. Others
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Cadmium Complexes: Rao et al. used the combination of the calix[4]arene derivative 56 and Cd2+ (Figure 32) [87] to fabricate an on–off fluorescence Cys probe, with a visual color change from blue to
M
dark. When Cys concentration was increased, the fluorescence intensity initially increased to a small extent, and then decreased gradually until it attained saturation, suggesting the involvement of –SH on
d
Cys in the binding of Cd2+, followed by its removal from the complex. Cellular studies using MCF-7
te
cells showed that this system can be utilized for in vivo imaging of Cd2+ and Cys.
Ac ce p
Aluminum Complexes: Xin and coworkers developed an Al3+ complex sensor based on bisrhodamine B thiourea conjugate 57 for Arg detection (Figure 33) [88]. Addition of Al3+ induced fluorescence enhancement, with the solution changing from colorless to pink through formation of the 1:1 57-Al3+ complex, with a binding constant (logKass) of 4.4. Among the AAs tested, only Arg completely quenched fluorescence, with the solution changing from pink to colorless, whereas the other AAs caused only a slight change on the emission and color of the 57-Al3+ complex. The 57-Al3+ complex exhibited a linear fluorescence on–off response to Arg that could be monitored up to 1.2×10−4 M. The off–on–off response of 57 to Al3+ and Arg is due to the stronger interaction of Arg with Lewis acidic Al3+, leading to the structural transformation of rhodamine B on 57 in the process of spiro ring structural formation (nonfluorescent)–ring opening (57-Al3+, strong fluorescence)–spiro ring structural formation (57-Al3+ + Arg). 25 Page 25 of 184
Edited May 11
Iron (Fe3+) Complexes: Addition of Fe3+ caused significant quenching in the monomer and excimer emission of 24 (Figure 11) [54], which was attributed to the PET process from pyrene units to carbonyl oxygen and the conformational changes of two pyrene-appended arms, respectively. The Fe3+(24) complex exhibited a significant increase in monomer and excimer emission intensities when Cys was
ip t
added. Complete revival of fluorescence emission is due to the complete removal of Fe3+ from the Fe3+(24) complex by Cys.
cr
Others: The chemosensing ensemble of 30-Zn2+ (section 4.1.2.1.) and 30-Cu2+ (section 4.1.2.2.)
us
underwent an on–off His sensing and an off–on Cys sensing, respectively [60], because of the dechelation of metal ions to form an His/Cys complex of metal ions. Rao and coworkers also utilized
an
the same strategy in the design of the Mn2+, Fe2+, Co2+, and Ni2+ complexes of 30, namely, [Mn230], [Fe230], [Co230], and [Ni230], which can be applied to AA sensing in a turn-on manner [60]. Among the
M
20 AAs investigated, [Co230] induced fluorescence enhancement of three AAs to different extents in the following order: His > Asp > Cys, with minimum detection concentrations {in ppm (µM)} of 0.53
d
(3.44), 0.34 (2.5), and 0.68 (5.65), respectively. [Mn230] signaled the recognition of Asp and Glu, with
te
minimum concentrations of 2.8 ppm (19.0 µM) for Glu and 2.67 ppm (20.2 µM) for Asp. [Ni230]
Ac ce p
exhibited high selectivity toward His over two AAs in the following order: His > Asp > Cys. [Fe230] showed no response to the AAs.
Insert Figure 32-33 Herein
4.1.3. Using Chemodosimeter Approach 4.1.3.1. Platinum Complexes
Lam et al. developed heterobimetallic chemodosimetric ensembles, 58, 59 and 60 (Figure 34) that could distinguish certain sulfhydryl-containing AAs/peptides [89], such as Cys, Hcy, Met and GSH, in 26 Page 26 of 184
Edited May 11
which the Pt(II) metal center acted as a functional-specific binding site that was bridged to the Mdiimine chromophore (M=Fe2+, Ru2+, Os2+) via cyano bridges. Upon an interaction with Cys, Hcy, Met and GSH, the luminescence of 58, 59 or 60 was increased and red-shifted due to the binding of the thiolcontaining AAs to the Pt(II) centers, and the subsequent cleavage of the cyano bridge and restoration of
ip t
the characteristic 3MLCT luminescence of Fe2+/Ru2+/Os2+-diimine chromophore. Complex 61 (Figure 35) [90] exhibited improved selectivity for Cys among 20 natural AAs investigated. The luminescence
cr
of 61 was quenched after interacting with Cys due to chloride displacement and the formation of the Pt-
us
S(Cys) bond. The lack of a response of 61 for Met was attributed to the hindered lone pair and lower nucleophilicity for the -SMe unit than the -SH group.
an
Phen has several appealing structural and chemical properties: rigidity, planarity, aromaticity, basicity and chelating capability. This makes it a versatile starting material for synthetic organic,
M
inorganic and supramolecular chemistry [91]. Phen, a weakly fluorescent molecule, has been used in the
such as Pt, Ru, Ir, etc.
d
design of many UV-Vis-NIR luminescent organic derivatives and coordination compounds with metals,
te
By incorporating Phen, the platinum(II) complexes of 62 (Figure 36) and 63 exhibited intense
Ac ce p
orange emission and green luminescence, respectively [92]. After adding Cys/Hcy, the emission of 63 was quenched and red-shifted from 510 to 555 with a luminescence color change from green to orange, due to the formation of a thiazinane group through a selective reaction of the aldehyde group of 63 with Cys/Hcy. The important role of the aldehyde group on 63 in interacting with Cys was confirmed by investigating the contrast complex of 62. Other AAs induced no obvious luminescence changes in 63 and the detection of Hcy/Cys was unaffected by the presence of 100 equiv. of other AAs or GSH.
Insert Figures 34-36 Herein
4.1.3.2. Iridium Complexes 27 Page 27 of 184
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These iridium complexes that applied in detecting AAs, were formed through coordinating two kinds of organic ligands with the iridium center. The reported examples are listed according to the ligands.
ip t
Using 4-(2-pyridyl)benzaldehyde (pba) as a co-ligand: Lo et al. reported a series of luminescent cyclometalated iridium(III) complexes (Figure 37) containing two aldehyde functional groups,
cr
[Ir(pba)2(N-N)](PF6) (N-N=2,2’-bipyridine, bpy (64), phen (65), 3,4,7,8-tetramethyl-phen (66), 4,7-
us
diphenyl-phen (67)) [93], which can conjugate with Ala. In their study, they did not examine the sensitivity and selectivity of the iridium(III) complexes 64-67 toward AAs. Therefore, the only
an
information could be obtained was that 64-67 were conjugated with Ala and induced changes in the emission spectra.
M
Li et al. reported a highly selective luminescent chemosensor (Figure 38), Ir(pba)2(acac) (68, acac=acetylacetone) [94] for Hcy over other AAs (including Cys) and thiol-related peptides (including
d
GSH). After titrating with Hcy, the emission band was blue-shifted, and the luminescence intensity was
te
increased due to a reaction of the aldehyde moiety with Hcy to form thiazolidines with an emission
Ac ce p
color change from deep red to green, which could be observed by the naked eye. Probes 69 (with pba and bpy liangds, Figure 38) [95] and 70 (with pba and phen-derived liangds, Figure 39) [96] and mesoporous silica-based nanoprobe 71 (with pba and 3-hydroxypicolinic acidderived liangds, Figure 40) [97] were used by Zhao, Huang, and coworkers as selective luminescent probes for Cys and Hcy over other AAs. The recognition mechanism involves the reaction of the aldehyde group in 69, 70, or 71 with the β-aminoalkylthiol and γ-aminoalkylthiol groups of Cys and Hcy to form the corresponding thiazolidine/thiazinane derivatives. Using 2-phenylpyridine and Phen/bpy-derived ligands: Che et al. reported that fluorescence resonance energy transfer (FRET)-based iridium complex 72 (Figure 41) [98] exhibits high selectivity for Hcy and Cys over the other 19 AAs and GSH. The luminescent emission of 72 (25 µM) was 28 Page 28 of 184
Edited May 11
increased up to 88-fold and 65-fold in the presence of Hcy (0 mM to 2.5 mM) and Cys (0 mM to 2.5 mM), respectively, because of the cleavage of the vinyl sulfide linkage of 72 by the nucleophilic Hcy or Cys (the vinyl sulfide linkage can only be cleaved by thiols, not by other nucleophiles, such as amines and alcohols [99]). The difference in emission intensity enhancement in the detection of Hcy and Cys by
ip t
probe 72 is attributed to a lesser bulky thiol group on Hcy than on Cys. Moreover, the iridium probe 73 with a tert-butyl group could differentiate Hcy from Cys at a ratio of 5:1 [98].
and
quantifying
Hcy+Cys
and
Trp
through
the
photoluminescence
(PL)
and
us
detecting
cr
As shown in Figure 42, Schmittel and Chen described the use of iridium complex 74 [100] for
electrochemiluminescence (ECL) channels, respectively. Complex 74 exhibited PL enhancement in the
an
presence of Hcy and Cys because of the aldehyde cyclization reaction. ECL quenching was observed at 602 nm in the presence of Trp because of its electroactivity.
M
The cyclometallated iridium complex 75 (Figure 43) [101], containing an α,β-unsaturated ketone moiety as a conjugated spacer, was used as a probe for the selective detection of thiols. For the 20
d
naturally occurring AAs, complex 75 showed specific selectivity toward thiols. For instance, the
te
luminescence intensity of 75 (20 mM) was enhanced 20-fold upon the addition of 80 equiv. of Cys
Ac ce p
because of the formation of a thioether in the adduct 76 by 1,4-addition of Cys to the α,β-unsaturated ketone of 75. The reactivity of the thiols to complex 75 showed the following trend: Cys > Hcy > GSH, which is consistent with the order of the steric hindrance effect. Using other ligands: Zhao, Li, Huang, and coworkers developed an ET-based iridium probe 77 (Figure 44) that can detect Cys and Hcy [102]. Probe 77 is non-emissive because of the ET process from the Ir3+ center and ligand 79 to the strong electron acceptor 2,4-dinitrobenzenesulfonyl (DNBS). Upon the addition of Cys and Hcy to probe 77, the luminescence of 78 is switched on because of the cleavage of the sulfonate ester of probe 77 by Cys and Hcy to form complex 78. Chao et al. developed a non-emissive dinuclear iridium complex 80 (Figure 45) [31] for the selective detection of thiols with mercapto groups, including Cys, Hcy, and GSH, under weakly acidic, 29 Page 29 of 184
Edited May 11
neutral, and weakly basic conditions, as well as imaging thiol levels in living cells. The phosphorescence intensity of 80 (5.0 μM) was enhanced 30-fold, 38-fold, and 35-fold upon the addition of Cys (50 μM), Hcy (50 μM), and GSH (50 μM), respectively, through the redox reaction between the
ip t
thiol and azo groups of 80.
cr
Insert Figures 37-45 Herein
us
4.1.3.3. Ruthenium Complexes
an
As luminescent probes, Ru(II) complexes have several desirable features including the intense visible absorption and emission, large Stokes shift, high photo-, thermal and chemical stability and very
M
low cytotoxicity [103-104]. Owing to these outstanding photochemical and photophysical properties, sensitive and selective luminescence probes based on Ru(II) complexes, particularly the Ru(II)-phen
d
complexes and Ru(II)-bpy complexes, have been developed for the recognition and detection of thiol-
te
containing AAs, such as Cys and Hcy, etc.
Ac ce p
Ru(II)-phen complexes: Lam et al. developed a heterobimetallic chemodosimetric ensemble, cisRu(phen)2-[CN-Pt(DMSO)Cl2]2
(81) (Figure 46) [105], that could be selective for sulfhydryl-
containing AAs and peptides, in which the Pt(II) metal center acted as a functional-specific binding site and was bridged to the indicator of the Ru(II)-diimine chromophore responsible for signal transduction. Complex 81 weakly emitted due to the coordination of two Pt(DMSO)Cl2 moieties to a Ru(II) center via cyano bridges. Upon an interaction with Cys, Hcys, Met and GSH, the luminescence of 81 was increased and red-shifted due to the binding of the thiol-containing AAs to the Pt(II) centers of 81, and the subsequent cleavage of the cyano bridge and restoration of the characteristic orange-red 3MLCT luminescence of Ru(II)-diimine chromophore. Zhao et al. used phosphorescent probe 82 (Figure 47) with an off–on switch effect for selective 30 Page 30 of 184
Edited May 11
detection of thiols [106]. Probe 82 is nonluminescent because of the efficient PET between the potent electron donor (Ru center) and strong electron acceptor (DNBS). The phosphorescence of 83 was switched on because the typical MLCT photophysics of the Ru2+ complex 83 with the N∧N ligand as electron acceptor was reestablished by cleavage of DNBS on 82 with thiols.
ip t
Ru(II)-bpy complexes: Yuan and Zhang et al. designed a DNBS-protected bpy-Ru2+ complex 84 probe for PL and ECL detections of Cys and GSH (Figure 48) [107]. Complex 84 emits weak MLCT-
cr
based PL because of the intramolecular PET process from the Ru2+ center to the electron acceptor
us
DNBS. Fluorescence turn-on in the presence of Cys and GSH is due to cleavage of DNBS by thiols, leading to recovery of MLCT-based luminescence of the complex 85. The probe was then applied to
an
detect biothiols in HeLa cells. Similarly, ECL enhancements were observed upon the addition of Cys and GSH. The FL and ECL intensities showed good linear relationships with the concentrations of Cys
M
and GSH, ranging from 0 µM to 10 µM for Cys and GSH. Through ECL titration, the LODs are 86.5 nM and 56.3 nM for Cys and GSH, respectively.
d
The cyclization reactions of Cys and Hcy with organic aldehydes on Ru2+ complexes have been used
te
to detect Cys and Hcy by forming thiazolidine and thiazinane derivatives. 86 with three aldehyde
Ac ce p
substituted bipyridine ligands (Figure 49), was designed for the selective recognition and sensitive detection of Cys/Hcy [108]. 86 was almost nonluminescent because the strong electron-withdrawing aldehyde group in the ligand can effectively quench the MLCT luminescence of the Ru2+ complex. 86 can react rapidly and specifically with Cys/Hcy to form the corresponding thiazolidine and thiazinane derivatives, resulting in a remarkable enhancement of MLCT emission and a large blue-shift in the maximum emission wavelength from 720 nm to 635 nm due to the disappearance of the electronwithdrawing effects of the aldehyde group. The ruthenium complexes 87-90 (Figure 50) [109] exhibited selective recognition of Hcy and Cys. For example, the emission intensity of 90 (7.0 μM) was enhanced 10.1-fold and 4.5-fold upon the addition of Hcy (0.7 mM) and Cys (0.7 mM), respectively. The formation of thiazinane and thiazolidine 31 Page 31 of 184
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played a key role in the selective recognition of Hcy and Cys, whereas little or no increase in luminescence was observed upon the addition of other AAs. All the complexes 87-90 were more sensitive to Hcy than Cys, probably because of the easier formation of thiazinane. Substitution with an electron-donating group (CH3) on bipyridine would also improve the recognition ability of the
ip t
complexes for Hcy and Cys. Chao, Ji, and coworkers reported that dinuclear Ru2+ complex 91 (Figure 51) can be used to probe
cr
thiols, such as Cys, Hcy, and GSH, over the other 19 natural AAs [110]. Complex 91 showed weak
us
luminescence because of the PET process. Upon exposure of 91 (10 μM) to Cys (0.2 mM), Hcy (0.2 mM), and GSH (0.2 mM), the luminescence intensity was enhanced by 35-fold, 36-fold, and 33-fold,
an
respectively, with the original gray color of 91 turning yellow because of the inhibition of the PET
M
process through reduction of the azo group into the azo2− form by these thiols.
te
Ac ce p
4.1.3.4. Copper Complexes
d
Insert Figure 46-51 Herein
Kang and Kim et al. reported the first copper complex, iminocoumarin-Cu2+ ensemble (92-Cu2+) (Figure 52) [111], used for thiol detection based on a chemodosimetric method. Owing to the thiol specific affinity of a copper ion, an off–on fluorescence change in 92-Cu2+ was observed by the addition of thiols (GSH, Hcy and Cys), which induced decomplexation of the Cu2+ ion from non-fluorescent 92, followed by the hydrolytic cleavage of 92 to yield a strongly fluorescent coumarinaldehyde 93 in aqueous solutions. Competitive experiments confirmed that the selective response of 92-Cu2+ to thiols was unaffected by the presence of other AAs. Chen et al. devised an iminofluorescein-Cu2+ ensemble probe 94-Cu2+ (Figure 53) for detecting Cys [112]. Fluorescent probe 94 exhibits a fluorescence quenching effect with Cu2+. The addition of 32 Page 32 of 184
Edited May 11
Cys induces the off–on-type fluorescence enhancement, which was ascribed to the decomplexation of the 94-Cu2+ ensemble, followed by hydrolysis of the Schiff base to form a strongly fluorescent fluoresceinaldehyde 95. The ensemble exhibited a similar response to other thiol-containing compounds, such as Hcy and GSH. Studies of biological applications showed that this system can be
ip t
utilized for the imaging of thiols in living cells.
us
cr
Insert Figures 52-53 Herein
an
4.2. Polymer-Metal Complexes
Compared with small organic-metal complexes, polymer-metal based systems have the capability to
M
improve the sensing performance. For example, polymer chains with multiple recognition elements can increase both the binding effieiency and recognition selectivity for specific AAs and polymer chains
te
d
with multiple signaling elements can enhance the sensitivity.
Ac ce p
4.2.1. Using Displacement Approach 4.2.1.1. Copper Complexes
4.2.1.1.1. Introducing Cu2+ binding sites into the polymer side chains
Li et al. developed imidazole-functionalized polyacetylenes 96 (Figure 54) [113] and 97 (Figure 54) [114] by introducing different functional moieties to the acetylene backbone as side groups to detect αAAs based on a turn-on model via an indirect approach. They also reported conjugated polymer-based fluorescent polyfluorene 98 (Figure 54) [115], which was applied as a chemosensor for indirectly detecting α-AAs. Cu2+ quenched the strong blue fluorescence of 96, 97, and 98 because of the affinity of imidazole moieties to Cu2+. Quenched fluorescence of 96, 97, or 98 was recovered by adding α-AAs to 33 Page 33 of 184
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the 96/Cu2+, 97/Cu2+, and 98/Cu2+ complexes, respectively; Cu2+ was captured from the complexes because of the formation of a stable 2:1 AA/Cu2+ complex [116]. 96/Cu2+, 97/Cu2+, and 98/Cu2+ complexes exhibited high sensitivity to His because of the affinity of imidazole moieties to Cu2+ ions. Fluorescence recoveries for 96, 97, and 98 were 88%, 92%, and 96%, respectively, which suggests that
ip t
96/Cu2+, 97/Cu2+, and 98/Cu2+ complexes could selectively probe His to some degree. Moreover, His can be differentiated from other α-AAs visually by observing the strong blue fluorescence using a
cr
normal UV lamp. Overall, although the selectivity of this system was relatively low, the β-, γ-AAs can
us
also induce the fluorescence recovery of 96, 97, or 98 to some degree, and the influence of β-AAs cannot be omitted. Importantly, this work might open up a new avenue to the development of new
an
biosensors. Fang et al. used the same strategy to design quinolinol-containing conjugated polymer 99 (Figure 54) [117], with side chains functionalized by imidazole, to sense AAs.
M
Gao et al. reported that Cu2+ complexes of conjugated polymer 100 can probe Cys, whereas Ni2+ complexes can probe His and Trp (Figure 55) [118]. Cu2+ or Ni2+ can bind with 100 to form 100-Cu2+
d
or 100-Ni2+ complexes, which consequently quenches the fluorescence of 100 because of the energy
te
from conjugated polymer backbone to Cu2+ or Ni2+ ions (i.e., PET process); the calculated Stern–
Ac ce p
Volmer constant Ksv is 4.6×106 M−1 for Cu2+ and 2.19×105 M−1 for Ni2+. Upon adding Cys to 100-Cu2+ complexes or His/Trp to 100-Ni2+ complexes, fluorescence of 100 was recovered by dissociating 100metal complexes and generating favorable and strong (Cys·Ni2+) or (Try·Ni2+) and (His·Ni2+) complexes.
Jayakannan’s group reported two water-soluble carboxylic functionalized distilbene chromophore bearing polymers 101 and 102 [119], which were utilized to sense AAs based on a turn-on model (Figure 56). Cu2+ traces efficiently quenched the strong blue fluorescence of 101 or 102. Six different AAs (i.e., Ala, Ser, Cys, Gln, His, and Trp) were added to 101-Cu2+ or 102-Cu2+ complexes, and quenched fluorescence of 101 or 102 was turned on. Although all six AAs could be detected sensitively, sensing activity depends on the nature of the AA side chain; the order of fluorescence enhancement is 34 Page 34 of 184
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His > Trp and Gln > Ala, Cys, Ser. His recovered high fluorescence intensity because the heterocyclic ring in His bound more strongly to Cu2+ compared with other AAs, while Cys attained saturation level quickly because of the thiophilic nature of Cys to Cu2+. Only 25% of fluorescence was recovered in this system because Cu2+-AA complexes formed incompletely and the thio-group in Cys strongly interfered
ip t
with His selectivity. Su et al. designed Cu2+ complex of water-soluble fluorescent conjugated polymer 103 as a turn-on
cr
fluorescent probe for Cys and GSH (Figure 56) [120]. Cu2+ quenched the fluorescence of 103 because
us
of the strong electrostatic interaction and ET between 103 and Cu2+. Upon adding Cys or GSH to 103Cu2+, the fluorescence of 103 was recovered because of the thiol functionality in Cys or GSH, which
an
can capture Cu2+ from 103-Cu2+ by forming Cu2+–S bonds.
Pitchumani and Azath constructed a flavone-modified β-cyclodextrin 104 that can selectively
M
detect His (Figure 57) [121]. Cu2+ ions induced strong fluorescence quenching of 104 because of the formation of a non-fluorescent Cu2+-104 complex. Upon adding D/L-His into the Cu2+-104 complex,
d
fluorescence intensity switched on because of the combination of D/L-His and Cu2+ and the release of
Ac ce p
te
104. Cu2+-flavone did not respond to His, which indicates that cyclodextrin cavity is key to sensing His.
Insert Figures 54-57 Herein
4.2.1.1.2. Using the ensembling strategy of DNA and Cu2+
DNA oligonucleotides, which are useful, functional, and structural elements, have recently been proposed to construct sensitive detection platforms for AAs. For example, Ren and co-workers developed single-stranded DNA-1/thiazole orange (105)/Cu2+ and DNA-1/105/Hg2+-based ensemble systems to detect His and Cys, respectively (Figure 58) [122]. 105 was non-fluorescent but exhibited intense fluorescence upon interaction with nucleic acids regardless of base composition. Fluorescence of 35 Page 35 of 184
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105/DNA-1 was quenched in the presence of Cu2+ (or Hg2+). Cu2+ (or Hg2+)-quenched fluorescence of 105/DNA-1 was then restored in the presence of His (or Cys) because of the formation of a stable complex between Cu2+ and His or Hg2+ and Cys. Most AAs do not interfere with fluorescence enhancement induced by His or Cys.
ip t
Ma and co-workers developed a DNA-2/iridium complex 106/Cu2+-based ensemble system (Figure 59) [123] for turn-on detection of His. Wang, Liu, and co-workers applied a similar approach to detect
cr
His using DNA-3/Cu2+/N-methylmesoporphyrin 107 ensemble (Figure 60) [124]. Emission of 106 or
us
107 was significantly enhanced in the presence of G-quadruplex, which implies selective interaction between 106 or 107 and G-quadruplex structure. Adding Cu2+ ions results in conversion of G-
an
quadruplex motif into single-stranded DNA (ssDNA) and diminished system emission. Among the 20 natural AAs, Hcy, and GSH, system luminescence was only restored upon adding His into ensembles
M
with N-ethylmaleimide (NEM) as a masking agent for Cys, Hcy, and GSH, because the sequestration of
te
Ac ce p
Insert Figures 58-60 Herein
d
Cu2+ preserves the G-quadruplex structure by forming a stable His-Cu2+ complex.
4.2.1.2. Mercury Complexes
4.2.1.2.1. Using the ensembling strategy of DNA and Hg2+
Ye et al. reported a new system for turn-on detection of biothiols with high sensitivity and selectivity based on a Tb3+/DNA-4/Hg2+ ensemble (Figure 61) [125]. Initially, guanine (G)/thymine (T)rich DNA-4 oligos ([G3T]5) sensitized Tb3+ luminescence via efficient intermolecular energy transfer from [G3T]5 ligand to Tb3+. Tb3+/[G3T]5 luminescence was then quenched by Hg2+ because of the interaction between [G3T]5 with Hg2+, which weakened the sensitizing responses of Tb3+ luminescence by [G3T]5. Luminescence gradually increased upon adding Cys in increasing concentrations to the 36 Page 36 of 184
Edited May 11
Tb3+/[G3T]5/Hg2+ ensemble. Turn-on luminescence response was due to the recovery of Tb3+/[G3T]5 luminescence by capturing Hg2+ via the formation of Hg2+-S bond. This ensemble had higher selectivity for biothiols (Cys, Hcy, and GSH) than the other 19 natural AAs and GSH disulfide (GSSG). An amount of Cys was added in artificial urine and serum samples with a recovery of Tb3+/[G3T]5
ip t
luminescence exceeding 95%, which was promising in practical applications. Leung and Ma et al. reported a G-quadruplex DNA-5/Ir3+ complex 108/Hg2+ ensemble (Figure 62)
cr
[126] to detect Cys and GSH with a tunable concentration range by varying Hg2+ concentrations. 108
us
was weakly emissive. However, its luminescence was enhanced significantly in the presence of Gquadruplex DNA-5 by forming 108–G-quadruplex ensemble. Adding Hg2+ to the 108–G-quadruplex
an
ensemble significantly quenched the luminescence because of various ET mechanisms. Cys or GSH restored the luminescence signal of the 108–G-quadruplex ensemble because thiol functional groups
M
could remove Hg2+ ions effectively from the G-quadruplex DNA-5/108/Hg2+ ensemble by forming strong Hg2+–S bond.
d
Double-stranded DNA (ds-DNA) formed by T-Hg2+-T base pairs has recently been applied to detect
te
biothiols. Hepel and co-workers designed ssDNA-6 oligonucleotide (Figure 63) [127] with
Ac ce p
carboxyfluorescein dye 109 and quencher 110 appended at 5’ and 3’ ends, respectively, to detect Cys and GSH. These oligonucleotides exhibited self-hybridized T-T mismatch after adding Hg2+, which formed a T-Hg-T structure. The fluorescence of 109 was quenched due to FRET, from 109 to quencher molecule 110, because of their close proximity. Adding GSH or Cys dissociated T-Hg-T because Hg2+ strongly binds with GSH/Cys, which spatially separated fluorophore 109 from quencher 110 and enhanced the fluorescence of 109. Moreover, fluorescence intensity was higher in the presence of GSH than in the presence of Cys, which suggests that GSH binds Hg2+ more strongly than Cys because of the extensive steric hindrance of GSH. Tang reported a Thioflavin T (111)/T-Hg2+-T system for detecting biothiols (Figure 64) [128]. 111/DNA-7 displays strong emission in which 111 induces quadruplex folding. Upon on the addition of 37 Page 37 of 184
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Hg2+ ions, the G-quadruplex folding is inhibited by the Hg2+-mediated formation of T–T base pairs, making the 111 stay in a free state and a weak fluorescence can bedetected. When biothiols was added, the 111/G-quadruplex ensemble was re-formed because stronger Hg–S interaction leads to dissociation of T-Hg2+-T base pairs.
ip t
Yao and Sun et al. also employed T-Hg2+-T base pairs to design biothiols probe based on GO/Ru complex 112/DNA-8 assembly (Figure 65) [129]. In a GO/112/ssDNA-8 assembly, fluorescence of 112
cr
was quenched because of the strong interaction between 112 and GO as the quencher. Adding Hg2+
us
formed dsDNA-8 via T–Hg2+–T base pairs, and 112 intercalated into newly formed dsDNA-8. 112 and dsDNA-8 were then removed from the GO surface, which restored fluorescence. Subsequently, adding
an
biothiols formed GO/112/DNA-8 assembly because of the high affinity of biothiol sulfur atoms to Hg2+.
M
T-Hg2+-T based pair was unwinded to produce ssDNA, which quenched the fluorescence of 112.
d
4.2.1.2.2. Using the formation and dissociation strategy of polymer-Hg2+ complex
te
Lee and coworkers proposed formed and dissociated conjugated polyelectrolytes 113−Hg2+−T assay
Ac ce p
to detect Cys (Figure 66) [130]. 113 exhibited a blue emission at 420 nm. A red emission at 653 nm was observed in the presence of Hg2+ and T, with decreased emission at 420 nm, which indicated intermolecular aggregates of 113 through the 113−Hg2+−T complex. This aggregation occurred because of the interactions of Hg2+ with 113 and Hg2+ with T, which formed T-Hg2+-T base pairs. Adding Cys reduced the red emission at 653 nm, and the blue emission was recovered at 420 nm, which suggests the dissociation of 113−Hg2+−T complex; Cys extracts Hg2+ from the assay complex through favorable binding between Cys and Hg2+.
Insert Figures 61-66 Herein
38 Page 38 of 184
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4.2.1.3. Silver Complexes 4.2.1.3.1. Introducing Ag+ binding sites into the polymer backbone
Bai et al. prepared Ag+ complexes of fluorescent conjugated polymers 114 and 115 (Figure 66)
ip t
[131], which contained 2,2’-biimidazole as coordination sites for Ag+, as ratiometric sensing platforms to detect Cys. 114-Ag+ and 115-Ag+ complexes decomposed upon the titration of Cys because Cys
an
4.2.1.3.2. Using the ensembling strategy of DNA and Ag+
us
cr
binds Ag+ through thiol–Ag+ interaction.
Luo and Li et al. [132], Hu and Zhou et al. [133-134] developed GO/DNA/Ag+ as a sensing platform
M
to selectively detect Cys from 19 other essential AAs. GO adsorbed cytosine (C)-rich unbound ssDNA9 and fluorescein derivative 109-labeled ssDNA-10 (Figure 67)132 by forming GO/DNA-9/DNA-10
d
complexes by stacking interactions between nucleotide bases and GO, which quenched the fluorescence
te
of 109. Fluorescence of 109 was significantly increased and red-shifted in the presence of Ag+ because
Ac ce p
of the formation of cytosine-Ag+-cytosine (C–Ag+–C) base pairs. C–Ag+–C structures unfolded upon adding Cys as a strong Ag+-binder and transformed dsDNA to two ssDNA, which were adsorbed on GO. Fluorescence was quenched, and the fluorescence emission wavelength was restored gradually. GO adsorbed C-rich fluorescein derivative 109-tagged ssDNA-11 (Figure 68) [133] and G-rich 109-tagged ssDNA-12 (Figure 68) [134] exhibited weak fluorescence because of FRET from 109/ssDNA-11 or 109/ssDNA-12 to GO. Introducing Ag+ recovered a large degree of fluorescence because of C–Ag+–C base pairs formation of 109/ssDNA-11 and G-Ag+ structure formation of 109/ssDNA-12; energy donor 109 was far from the GO surface, and FRET disappeared. Fluorescence of 109 was quenched again in the presence of Cys because FRET recovered from the strong binding between Cys and Ag+. The binding removed Ag+ from the C–Ag+–C base pairs, and the G-Ag+ structure 39 Page 39 of 184
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was destroyed. Shi et al. recently employed Tb3+/DNA-4/DNA-13/Ag+ sensing system to detect Cys (Figure 69) [135]. Luminescence of dsDNA/Tb3+ ensemble Tb3+/[G3T]5/C[G3T]5 was turned on in the presence of Ag+ because of the strong interaction of Ag+ with C[G3T]5. This interaction formed a C–Ag+–C
ip t
complex that liberated [G3T]5 from the [G3T]5/C[G3T]5 duplex and resulted in Tb3+/[G3T]5 luminescence. C–Ag+–C complex decomposed upon adding Cys because of the binding between Cys
cr
and Ag+, and fluorescence was quenched again. No obvious luminescence decrease was observed with
us
the other AAs, which indicates that the Tb3++[G3T]5/C[G3T]5+Ag+ sensing system is suitable for
an
specific detection of Cys.
M
Insert Figures 67-69 Herein
4.2.1.4. Cobalt complexes
te
d
4.2.1.4.1. Introducing Co2+ binding sites into the polymer side chains
Ac ce p
Lee et al. reported Co2+-mediated hyperbranched polymer 116 as a sensing platform to detect Cys (Figure 70) [136]. Co2+ quenched the emission of 116 by forming 116–Co2+ complex through the interaction of Co2+ and sulfonic acid groups of 116. 116–Co2+ was dissociated to generate a favorable and strong Cys–Co2+ complex by adding Cys. However, Cys induced complete emission quenching of 116 instead of restoring its original fluorescence because of the absorption screening effect of the CysCo2+ complex, which prevents 116 from absorbing excitation energy.
Insert Figure 70 Herein
4.2.2. Using Chemodosimeter Approach 4.2.2.1. Iridium Complexes 40 Page 40 of 184
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Zhao, Huang, and coworkers [32] utilized water-soluble iridium complex-functionalized poly(Nisopropylacrylamide) 117 (Figure 71) in sensing Hcy and Cys from the interaction between aldehyde groups on 117 and thiol groups to form thiazolidine or thiazinane ring [137]. Among the various AAs,
ip t
only Cys and Hcy induced fluorescence enhancement with a blueshift from 567 to 558 and from 567 to 554, respectively. 117 can also be applied in quasi-solid state to sense Hcy and Cys, with visible color
cr
change from orange to yellow using polymer hydrogel.
us
Subsequently, Zhao, Huang, and coworkers developed another chemodosimeter for Cys and Hcy based on water-soluble phosphorescent polymer 118 (Figure 72) [138] by introducing an iridium
an
complex as a phosphorescent signaling unit. The design was based on the fact that iridium complex monomers contain aldehyde groups and could react with β- and γ-aminothiol groups to form
M
thiazolidine and thiazinane, respectively, which result in changes in emission intensity of the iridium
te
Ac ce p
Insert Figures 71-72 Herein
d
complex, thereby facilitating the detection of Cys and Hcy.
4.2.2.2. Metal-Organic Frameworks (MOF)
Wang and Feng et al. recently synthesized a new metal–organic framework (MOF) 119-ZIF-90 (Figure 73) by linking malonitrile (119) to zeolitic imidazolate frameworks (ZIFs) [139]. 119-ZIF-90 is the first fluorescent MOF probe to detect H2S and selectively recognize Cys. Fluorescence of ZIF-90 quenched through intramolecular PET, which produced double bond linkages of 119 and ZIF-90. Fluorescence enhanced 3.3-fold and 8.5-fold upon immersing 119-ZIF-90 (0.2 mM) in a solution of H2S (0.2 mM) and Cys (0.2 mM), respectively, because of adding thiol compounds to α, β-unsaturated 119, which resulted in broken double bonds. Other AAs investigated in this work only exhibited small 41 Page 41 of 184
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fluorescence enhancement. The system was also applied to recognize biothiols in biological systems through fluorescence microscopy studies.
ip t
Insert Figure 73 Herein
cr
5. Hybrid Organic-Metal Nanoparticles/Nanoclusters
us
In the last decade, fluorescent/luminescent nanoparticles/nanoclusters [140-143] have emerged as a new class of fluorophores with the potential to overcome the limitations of conventional fluorophores,
an
such as photobleaching, limited brightness (the product of extinction coefficient and fluorescence quantum yield) and short lifetimes. By functionalizing the organic part on the metal nanoparticles, the
M
surface chemistry of the nanoparticles can be tuned to create chemical specificity, which is a key
d
requirement for successful sensing and imaging platforms [143].
te
5.1. Small Molecule-Functionalized Metal Nanoparticles/Nanoclusters
Ac ce p
5.1.1. Using Binding Site-Signaling Subunit Approach 5.1.1.1. Gold Nanoparticles
Thomas et al. synthesized the photochromic spiropyran functionalized Au nanoparticles (Au-SP) (Figure 74) [144-145] for the assembly and release of an AA derivative upon irradiation. Under dark conditions, the majority of spiropyran molecules exist in their “closed” spiro form (SP, colorless and nonpolar), which when excited with UV light, undergoes photoisomerization to the “open” merocyanine form (MC, highly polar and zwitterionic) and absorbs in the visible region. Ring closure to the spiropyran form can occur either thermally or by exposure to visible radiation. After binding with charged AAs, the emission intensity of Au-MC decreased gradually with time, and the solution became 42 Page 42 of 184
Edited May 11
practically non-fluorescent after 120 min. The Au-MC/AA complex dissociates upon photoirradiation at 520 nm and undergoes thermal ring closure to Au-SP, releasing the AA derivatives. The complexation/dissociation cycles could be repeated many times. Light-mediated binding and the release of AA derivatives on the nanoparticle scaffold, in combination with the site specificity of the Au
ip t
nanoparticle, offers a unique possibility of designing light-mediated controlled release systems. On the other hand, only a few AAs were studied, and the sensitivity and selectivity of Au-SP toward specific
us
cr
AAs were unknown.
an
Insert Figure 74 Herein
M
5.1.1.2. Quantum Dots
Semiconductor quantum dots (QDs) [146-149] have emerged as an attractive fluorescent material
d
over the past two decades. A comparison with organic dyes and fluorescent proteins revealed QDs to
te
have a high emission quantum yield, size-dependent wavelength tunability, broad excitation spectrum,
Ac ce p
narrow/symmetric emission spectrum, high photobleaching threshold and excellent photostability. These advantages make QDs ideal fluorescent indicators for chemical and biological assays. Previous studies of the interactions between QDs and metal ions reported that surface capping ligands had a profound effect on the luminescence response of QDs to physiologically important metal cations. Therefore, specific sensing of analytes can be achieved by the proper choice of QDs surface ligands. In 2009, He et al. prepared monodisperse and homogeneous mercaptoacetic acid (MAA)-capped CdSe/ZnS QDs (MAA-QDs) [150] for L-Cys detection. An increase in the fluorescence intensity of MAA-QDs was observed in the presence of L-Cys (10-800 nmol L-1). No interference to coexisting foreign substances including common ions, carbohydrates, nucleotide acids and other 19 AAs was observed. Moreover, their method has been applied successfully to the determination of L-Cys in 43 Page 43 of 184
Edited May 11
clinical and biological samples. In 2011, Wang et al. reported that the probe, sodium citrate (Cit)-capped CdS QDs [151], offered good sensitivity and selectivity for the detection of Cys. In the presence of Cys, the coordination of a mercapto group with Cd2+ through the formation of Cd-S bonds led to the adsorption of Cys onto the
ip t
surface of CdS nanocrystals, resulted in an increase in the fluorescence intensity of Cit-capped CdS QDs (4.0×10−5 M) with Cys from 1.0×10−8 M to 5.0×10−5 M. Another sulfur-containing AA, Met, as a
cr
control molecule, did not affect the fluorescence of Cit-CdS even at high concentrations. This is because
us
the sulfur atom in Met is flanked by a methyl group and amethylene group on the two sides, which hindered the interaction between Cd and sulfur. Moreover, other AAs (such as Arg and His) showed
5.1.2. Using Displacement Approach
d
5.1.2.1. Gold Nanoparticles/Nanoclusters
M
an
almost no interference on the detection of Cys at high concentrations.
te
Gold nanoparticles (Au NPs) have a high extinction coefficient in the visible region. These
Ac ce p
extraordinary optical features make Au NPs an ideal color reporting group for signaling molecular recognition events and making them function as efficient quenchers for most fluorophores [152-156]. Dong et al. reported a NIR fluorescent method [157], that can be used for the detection of thiols in plasma, which is based on a thiols-modulated interaction between NIR fluorescent dye 120 and Au NPs (Figure 75). The fluorescence emission of 120 was decreased dramatically in the presence of Au NPs with a 2 nm-blue-shift. This was attributed to ET because slight overlap between the emission spectra of 120 and the absorption spectra of the Au NPs. With increasing Cys concentration, the fluorescence intensity of 120 increased gradually due to the strong affinity of thiol to gold over a Au-N interaction that the adsorbed 120 was replaced by Cys. As a result, Cys was favorably capped on the surface of the Au NPs, and 120 was released to the solution. Hcy and GSH with thiol groups also produced an 44 Page 44 of 184
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enhanced fluorescence signal, whereas there was almost no observable change in fluorescence upon the addition of the other AAs without thiol groups. GSH exhibited a relatively low reaction activity compared with Cys and Hcy, which might be due to steric hindrance. Song and coworkers fabricated Ni2+-modified Au nanoclusters (NCs) to fluorescence turn-on
ip t
detecting His, in urine samples (Figure 76) [158]. Bovine serum albumin (BSA)-capping Au NCs emitted red fluorescence under UV light (365 nm). Fluorescence of BSA-Au NCs was quenched by Ni2+
cr
and restored by His. A nonfluorescence groundstate complex formed between Ni2+ with the BSA–Au
us
NC surface and the dissociation of Ni2+ from the Au NCs surface by coordinating His with Ni2+.
an
Insert Table 2 and Figures 75-76 Herein
M
5.1.2.2. Silver Nanoparticles
detect low and high molecular weight thiol-containing biomolecules
te
spheres (Figure 77) [159]
d
Yu et al. reported that the formation of 121/Ag NPs/carbonaceous nanospheres (C NPs) hybrid
Ac ce p
selectively and sensitively, including Cys, GSH, dithiothreitol and BSA, upon a place-exchange process between 121 on the surface of the Ag NPs and the thiol groups of thiol-containing biomolecules. On the other hand, the fluorescence intensity of the solution remained unchanged in the presence of other AAs and monosaccharides, indicating that the amino and carboxyl groups in the AAs as well as the hydroxyl and aldehyde groups in the monosaccharides cannot effectively place exchange 121 molecules on the surface of the Ag NPs. Cys showed a significantly higher fluorescence ratio (F/F0), showing that the thiol functionality in Cys is essential for spectral changes.
Insert Figure 77 Herein
45 Page 45 of 184
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5.1.2.3. Quantum Dots
Wu and Yan synthesized Hcy-capped CdTe QDs (Figure 78) [160] through covalent binding of the thiol groups of Hcy with Cd2+ of CdTe core using the modified Rogach–Weller method [161-162]. Ni2+-
ip t
modulated Hcy-capped CdTe QDs based turn-on PL sensor was applied successfully to determine His in human urine samples. PL of Hcy-capped QDs was quenched rapidly upon adding Ni2+ because the
cr
coordination of Ni2+ with primary amine and the carboxylic group of Hcy eventually brought Ni2+
us
proximal to QDs, which resulted in a short range ET from excited Hcy-capped CdTe QDs to Ni2+. His restored the Ni2+-quenched PL of Hcy-capped CdTe QDs because of the high affinity of His to Ni2+,
an
which dissociated Ni2+ from the Hcy-capped CdTe QDs surface. The developed turn-on mode QD-based PL sensor had higher selectivity for His over the other AAs. Biothiol interference can be eliminated by
M
diluting samples or by blocking the biothiols with NEM.
Su’s group developed a simple and efficient fluorescence turn-on assay [163] to detect biothiols
d
(GSH and L-Cys), His, and threonine (Thr) in PBS buffer and in human serum samples based on an
te
indicator-displacement assay (IDA) and Cu2+–biothiols (GSH and L-Cys), His, or Thr affinity pairs
Ac ce p
(Figure 79). This approach employs Tyr-functionalized CuInS2 QDs (T-CuInS2 QDs) as indicators, and biothiols (GSH and L-Cys), His, or Thr were selectively detected based on the competition between indicator and biothiols (GSH and L-Cys), His, or Thr in binding with Cu2+. The competition of biothiols (GSH and L-Cys), His, or Thr with T-CuInS2 QDs for Cu2+ resulted in the fluorescence restoration of T-CuInS2 QDs; restoration ability followed this order: GSH > Cys > His > Thr. Su’s group employed the same strategy in designing a dopamine-functionalized CdTe QDs (DA QDs) as a fluorescence probe to determine L-His (Figure 80) [164]. The probe displayed fluorescence quenching in the presence of Ni2+. Ni2+-promoted fluorescence quenching was inhibited by adding His. Tian et al. utilized CdTe/CdS QDs-phen complex [165] for selective detection of PL turn-on of Cys and HCy (Figure 81). Phen induced fluorescence quenching of CdTe/CdS QDs because of the formation 46 Page 46 of 184
Edited May 11
of nonfluorescent complexes of CdTe/CdS QDs-Phen. Phen was displaced from the QDs surface after adding Cys or Hcy because of the strong affinity of Cys and HCy to CdTe/CdS QDs. The complex showed a good linear relationship between PL intensity of QDs and concentration of Cys (1 μM to 70 μM) and HCy (1 μM to 90 μM). Among AAs, proteins, metal ions, carbohydrates, nucleotides, and
ip t
thiol-containing compounds, only Cys and Hcy were able to increase fluorescence at a concentration of 0.8 mM, which demonstrates superior selectivity of the system for Cys and Hcy. Cys was determined in
cr
human serum samples to evaluate the applicability of the present sensing assay in biological samples.
us
The method provided good recoveries from 84.7% to 115.9%, which indicates reliability and practicality to detect cysteine in biological fluids.
an
Zhong, Li, and coworkers designed a fluorescent sensor to detect biothiols via ET between CdTe/CdS QDs and TiO2 NPs (Figure 82) [166]. The coupling of mercapto propionic acid (MPA)-
M
capped QDs with TiO2 quenches QDs fluorescence because of the covalent bonding between the terminal carboxyl group of MPA ligands and the Ti atom on the surface of TiO2 NPs, which induced
d
electron injection from QDs to TiO2. When thiols were introduced to the QD–TiO2 composite system,
te
quenched fluorescence of QD was switched on by replacing MPA on the QDs surface with thiols
pathway.
Ac ce p
because of the strong coordination of thiols with metal ions on the QD surface, which interrupted the ET
Insert Figures 78-82 Herein
5.2. Polymer-Functionalized Metal Nanoparticles/Nanoclusters 5.2.1. Using Binding Site-Signaling Subunit Approach 5.2.1.1. DNA-Templated Silver Nanoclusters
Few-atom, molecular-scale noble metal NCs are a class of emitters that simultaneously exhibit 47 Page 47 of 184
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bright, highly polarizable discrete transitions and possess good photostability and small sizes within biocompatible scaffolds [167-168]. Han and Wang reported fluorescent Ag NCs stabilized by ssDNA14 (5’-AATTCCCCCCCCCCCCAATT-3’) (DNA-14/Ag NCs) [169]. PL intensity of DNA-14/Ag NCs was quenched effectively by increasing biothiol concentration because of the formation of
ip t
nonfluorescent coordination complex between DNA-14/Ag NCs and biothiols, which resulted in a redshift in the emission wavelength. DNA-14/Ag NCs had high selectivity for biothiols because no
cr
quenching responses to the other 19 α-AAs were observed. Moreover, the method was successfully
us
detected thiols in human plasma samples, which suggests that the approach is practical for diagnostic purposes.
an
Ren, Xu et al. reported turn-on fluorescence of DNA-15 templated Ag NCs, dC12-Ag NCs, with increasing concentrations of thiol compounds (Cys, Hcy, and GSH) (Figure 83) [170]; the enhancement
M
followed the order, Hcy > GSH > Cys, which is parallel to the order of charge donating ability of thiol compounds. Turn-on fluorescence of dC12-Ag NCs by thiols was due to a charge transfer from the
d
ligands to the metal center via Ag-S bonds and to the contribution of other electron-rich groups (–
te
COOH, –NH2) in the thiol groups. Fluorescence enhancement is also due to changes in the
Ac ce p
microenvironment of the dC12 template because of addition of thiol compounds. By contrast, the other 19 AAs or biologically relevant analytes exhibited no obvious enhancement. The observed high specificity is due to specific and robust interaction between Ag and thiol compounds. Fluorescence response pattern of Ag NCs to a specific analyte significantly depends on the nature of the DNA template. Enhanced fluorescence was observed for Ag NCs formed in a series of polycytosine DNA (DNA-15, 16, 17, 18) upon adding thiol compounds; nearly no fluorescence variations of AgNCs formed in DNA-19 and DNA-20, and fluorescence of DNA-21, 22, 23, 24 templated AgNCs decreased (Figure 83).
Insert Figure 83 Herein 48 Page 48 of 184
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5.2.1.2. DNA-Templated Copper NanoClusters
Chu and coworkers reported dsDNA-templated Cu NCs as a fluorescence probe to detect biothiols
ip t
(Figure 84) [171]. PL intensity of DNA-CuNCs was quenched effectively by increasing biothiol concentration because of the formation of nonfluorescent coordination complexes between DNA-Cu
cr
NCs and biothiols. The resulting calibration plots exhibited good linear correlations from 2.0×10−6 to
us
1.0×10−4 M for Cys, 2.0×10−6 to 8.0×10−5 M for GSH, and 5.0×10−6 to 2.0×10−4 M for Hcy. The method
an
was successfully applied to detect biothiols in human plasma samples.
M
Insert Figure 84 Herein
5.2.2. Using Displacement Approach
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d
5.2.2.1. Polymer-Templated Gold Nanoparticles/Nanoclusters
Ac ce p
Over the last decade, the application of Au NPs and water-soluble fluorescent polymers has attracted considerable attention due to their unique performance for use as highly sensitive chemical and biosensors [172-176]. The composited polymer-Au NPs have been appled in detecting AAs. Water-soluble anionic fluorescent conjugated polymer 122-stabilized Au NPs (122-Au NPs) (Figure 85) [177] was used to sensitively and selectively detect Cys. In this system, 122 not only functioned as a photoactive fluorophore, but also as a good protective agent for colloids because they can combine steric and electrostatic stabilization into electrosteric stabilization. Moreover, Au NPs did not aggregate from the steric effects of 122. The fluorescence of 122 was weak because of highly efficient FRET between 122 and Au NPs. Consequently, fluorescence of 122 was recovered by increasing Cys concentration because of the strong interaction between the thiol group of Cys and gold and 122 moved 49 Page 49 of 184
Edited May 11
away from the Au NP surfaces. The control experiments showed that Cys had a negligible effect on the emission of 122 alone. Therefore, increased fluorescence did originate from the modulation of ET between 122 and gold where 122 acted as an amplifier. Importantly, 122 contributed to the low LOD. Among the other 19 AAs, Met exhibited a relatively large increase in fluorescence because of the weak
ip t
interaction between the S-CH3 group and Au NPs. Fluorescence in the presence of the other 19 AAs all increased less than 5% relative to Cys at the same concentration (3.0 μM). Other thiol molecules (e.g.,
cr
2-mercaptoethanol and thioglycolic acid) also increased fluorescence intensity of the 122-Au NPs
us
solution, which suggests that the thiol group of Cys has an important role in the system. Guan et al. developed the sensitive and selective detection of Asp and Glu based on polythiophene
an
(123)-Au NPs composites (Figure 86) [178]. When a wine-red colored Au NPs solution was added to a yellow aqueous solution of 123, the fluorescence of 123 could be quenched dramatically by Au NPs,
M
even at very low concentrations through highly efficient ET between them. The KSV value was 1.29×1010 M−1 with concentrations ranging from 0 pM to 26 pM. Only Asp and Glu could recover the
d
quenched fluorescence of among 20 AAs investigated because of the acidic properties of Asp and Glu,
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and 123 was released from the 123-Au NPs composites to emit fluorescence.
Ac ce p
Park and coworkers developed BSA-stabilized Au NCs as turn-on fluorescent sensors to detect biological thiol (Figure 87) [179]. Hg2+ ions quenched the red fluorescence of Au NCs via high-affinity metallophilic Hg2+–Au+ interactions. Biological thiols captured Hg2+ ions via a robust Hg–S interaction, which prevented Hg2+-induced quenching and resulted in Au NC fluorescence.
Insert Figures 85-87 Herein
5.2.2.2. Polymer-Templated Silver Nanoclusters
Shang and Dong produced water-soluble Poly(methacrylic acid, sodium salt) (124)-templeted Ag 50 Page 50 of 184
Edited May 11
NCs using as a fluorescent sensor for Cys (Figure 88) [180]. 124-stabilized Ag NCs displayed a maximum fluorescence emission at approximately 615 nm, which originates from the inter-band transitions from the submerged and quasi-continuum 5d band to the lowest unoccupied conduction band of the Ag NCs [181-182]. With increasing Cys concentration, the fluorescence emission of the 124-Ag
ip t
NCs decreased gradually and was almost completely quenched in the presence 6.0×10-5 M Cys with an obvious red-shift in the emission maximum. This was attributed to the thiol-adsorption-accelerated
cr
oxidation of emissive Ag NCs. The present assay allows for the selective determination of Cys in the
us
range of 2.5×10−8 to 6.0×10−6 M.
Luo and Li et al. synthesized water soluble polyethyleneimine 125-capped Ag NCs (Figure 88)
an
[183] that could selectively recognize thiols (i.e., Cys, Hcy, and GSH among 20 natural AAs, Hcy, and GSH) based on the interaction of silver ions with amino groups of 125. NCs agglomerated upon adding
M
thiols because the adsorbed biothiols on 125-Ag NCs freed the Ag NCs and lowered surface charge, which resulted in large nonfluorescent NPs with average diameters of 110 nm and various geometries.
d
Fluorescence intensity of 125-Ag NCs was gradually quenched by increasing biothiol concentration.
te
Linear ranges for Cys, Hcy, and GSH were 0.1 mM to 10 mM, 0.1 mM to 10 mM, and 0.5 mM to 6
Ac ce p
mM, respectively. Sensitivity (Cys, Hcy > GSH) was rationalized on the basis of steric effects on GSH chemisorption on 125-Ag NCs. 125-Ag NCs were further investigated for its ability to detect biothiols in human plasma samples.
Sun et al. applied human serum albumin (HSA)-stabilized gold-core silver-shell nanocrystals (HSAAu/Ag NCs) (Figure 89) [184] to determine the concentration of [Cys plus HCy] in spiked solutions of biomolecules and real biological samples. Adding Cys (or HCy) quenched NC luminescence because Cys or HCy adsorbed on the surface through ligand exchange with HSA.
Insert Figure 88-89 Herein
51 Page 51 of 184
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6. Chiral/Enantiomeric Recognition
AAs play undeniable roles in a wide range of bioscience areas and food analysis [185]. AAs can be present as L- or D-isomers. Although the D-amino acids (D-AAs) and L-amino acids (L-AAs) have
ip t
similar physical characteristics and chemical properties in nonstereo environments, they can have quite different pharmacological properties and bioactive effects in stereo environments, particularly in
cr
biological environments. This is why the U.S. Food and Drug Administration (FDA) has laid down
us
strict guidelines on the identification and quantification of chiral compounds [186-189]. Therefore, enantioselectivity is one of the most important goals for the sensing of organic substances [190-198],
an
because biological activity is strictly correlated with stereochemistry. Although some enantioselective methods based on capillary electrophoresis [199-200], voltammetry [201], colorimetric methods [202-
M
204] etc. have been proposed, there are examples of enantioselective fluorescence sensors [205-206]. Fluorescent sensors that can differentiate the two enantiomers of a chiral compound should provide
d
a real time technique for rapid chiral assays with many unique advantages compared with the ESI-MS
te
spectra, NMR, UV-Vis and electrophoresis [207-210]. The chiral recognition of AAs and peptides is a
Ac ce p
fundamental process for regulating various functions in living systems, particularly in connection with the application of high throughput combinatorial techniques [211]. Three possible methods achieve the chiral recognition of AAs in fluorescence/luminescence using fluorescent/luminescent sensors [212-215] that are generally composed of a fluorophore (indicator) and a binding site (receptor): (1) the introduction of chirality into the binding site of the sensor that could carry out the enantioselective recognition of chiral AAs; (2) labeling the chiral AAs with the fluorescence indicator that can be discriminated in the presence of the chiral receptor; and (3) the use of enantioselective indicator displacement assays.
6.1. Using Binding Site-Signaling-Subunit Approach 52 Page 52 of 184
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6.1.1. Introducing Chirality into the Binding Site of the Sensor 6.1.1.1. Introducing Chirality into Dansylated Cyclodextrins
Corradini et al. used dansylated cyclodextrins as tools for the development of enantioselective
ip t
fluorescent sensors of AAs or AA derivatives [216]. In these cyclodextrin derivatives, the ligands are terdentate, with an amide, amine, and sulphonamide group as Cu2+ binding sites. The Cu2+ ion may in
cr
turn act as a binding site for bifunctional moieties, particularly α-AAs. An additional chiral center was
us
present in the side arm, which could enhance the enantioselectivity. The dansyl group was selected as a fluorophore, which could interact with both the cyclodextrin cavity and Cu2+ ion.
an
In 2000, Corradini et al. reported that the fluorescence of two dansyl-modified cyclodextrins (R)126 and (S)-126 (Figure 90) [217] was quenched by forming non-fluorescent copper complexes, Cu-
M
(R)-126 and Cu-(S)-126, with the Cu2+ coordinated by the amino, amide and sulfonamide groups. An
d
increase in fluorescence was observed upon the addition of D- and L-AAs to Cu-(R)-126 and Cu-(S)-
te
126 at a 1:1 ratio. Complex Cu-(S)-126 showed better discriminating properties than Cu-(R)-126. In particular, Cu-(S)-126 was enantioselective for Pro, Phe and Trp. The best enantioselectivity of Cu-(S)-
Ac ce p
126 was observed for Pro with a reversed order (∆FD/∆FL=3.89) in the concentration range analyzed (6×10-5 M - 6×10-4 M). The enantioselectivity of Cu-(S)-126 for Pro was opposite to that observed for Phe (∆FD/∆FL=0.33) and Trp (∆FD/∆FL =0.63). A negligible difference was found between the two enantiomers of Ala, which bears a small aliphatic side chain, suggesting possible involvement of the cyclodextrin cavity in complex formation. In the case of His, a large increase in fluorescence was observed for both enantiomers on account of its strong histamine-like (amino and imidazolyl groups) binding sites. In 2004, the same research group examined the fluorescence sensing mechanism [218] of 126 as a function of the analyte AA and cyclodextrin structure. The enantioselectivity in the fluorescence response was attributed to the formation of diastereomeric ternary complexes. A comparison of 126 and the analogous compound 127, without a cyclodextrin part, provided important 53 Page 53 of 184
Edited May 11
insights into the role of the cavity in the recognition process. Based on the observation of 126, Corradini et al. then synthesized dansylated cyclodextrin derivatives (Figure 91) with rigid chiral side arms derived from AA synthons (AA = L- and D-phe (L126 and D-126), L- and D-phenylglycine (L-128 and D-128), L-pro (L-129), and L-cyclohexylglycine
ip t
(L-130)) [219] to increase the enantioselectivity. 128, 129 and 130 showed higher fluorescence than 126 under the same conditions, suggesting that a linker with a more rigid structure favors the self-inclusion
cr
of the dansyl group within the cyclodextrin cavity or provides a higher shielding effect of the
us
fluorophore, which is quite promising for the overall sensitivity of the sensing process. The enantioselectivity was evaluated by the addition of Cu2+ complexes of D- or L-val and D- or L-pro. The
an
L-AA containing cyclodextrins exhibited better enantioselectivity than D-AA containing cyclodextrins, some of which were higher than those already reported for 126. L-126, L-128, L-129 and L-130 showed
M
significant enantioselectivity in the fluorescence responses of both Pro and Val. The enantioselectivity was reversed for the two AAs (FL < FD for Pro and FL > FD for Val). The best enantioselectivity was
d
obtained with 130 for Pro and with 129 for Val, indicating that the insertion of more rigid and sterically
te
constrained structures (cyclohexylglycine and Pro) in the side arm is an efficient strategy for improving
Ac ce p
the enantioselectivity. Overall, the formation of a ternary diastereomer and the biasing effect of the cyclodextrin cavity in these chiral selectors were proposed [219]. The rapid, simple and low-cost technology of fluorescence microplate readers was also used to screen the samples with high enantiomeric excess using 128 [220].
Insert Table 3 and Figures 90-91 Herein
6.1.1.2. Introducing Chiral Molecules as Binding Sites
Xu and coworkers synthesized salan probe 131 to detect α-AAs (Figure 92) [221]. Fluorescence of 54 Page 54 of 184
Edited May 11
131 enhanced in the presence of CuCl in ethanol, which was attributed to Cu+-triggered π–π interaction of aromatic rings on 131 and formation of 131-Cu+ complex. In situ generated CuCl complex of 131 interacted with D/L-Leu and D/L-Pro via the Cu+ center, which decreased excimer fluorescence intensity. In situ generated CuCl2 complex of 131 enantioselectively recognized D-leucine (Leu) and L-
ip t
Leu through turn-on (D-Leu) and turn-off (L-Leu) fluorescence response mode. Fluorescence of
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Cu(OAc)2–131 complex was also enhanced in the presence of Phe and Pro AAs.
us
6.1.1.3. Introducing Chirality into Quantum Dots
an
Xia and coworkers reported a fluorescent sensory system to discriminate L-/D-Cys (Figure 93) [222] based on the assembly formation between D-Cys (or L-Cys) modified CdTe@CdS QDs (L-QDs
M
or D-QDs) NPs and gold nanorods (GNRs). L-QDs or D-QDs mixed with GNRs emitted strong fluorescence in NIR wavelengths. Cys induced efficient FRET from QDs to GNRs through the
d
formation of QD-GNR assembly, which quenched the fluorescence intensity of QD/GNR.
te
Enantiodiscrimination of Cys was observed through different quenching degrees of fluorescence. In
Ac ce p
practice, L-QD/GNR-based sensors exhibited distinct enantioselectivity to Cys, whereas D-QD-GNR exhibited reversed enantioselectivity to Cys (i.e., L-Cys quenched D-QD-GNR fluorescence stronger than D-Cys did). The results demonstrate that heterochiral (L- and D-Cys) interaction results in more notable FRET efficiencies compared with homochiral (L−L or D−D-Cys) interaction. The mechanism of QD/NR assemblies was confirmed further because thiol-free AAs and small thiol molecules led to a small decrease or no decrease in fluorescence. Moreover, the present sensing platforms determined both enantiomeric composition and concentration of Cys.
Insert Figures 92-93 Herein
55 Page 55 of 184
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6.1.2. Labeling Amino Acids Enantiomers with the Fluorescence Indicator
Lv et al. reported fluorescent water-soluble L-GSH-stabilized Ag NCs [223] for chiral recognition of D- and L-Cys based on effective PET between Ag NCs and L-Cys. Fluorimetric titration experiments
ip t
demonstrated that L-GSH–Ag NCs displayed excellent performance on enantioselective discrimination among enantiomers of Cys. For example, obvious fluorescence quenching of Ag NCs was observed in
cr
the presence of L-Cys. However, adding D-Cys scarcely influenced Ag NCs fluorescence. The
an
6.2. Using Enantioselective Indicator Displacement Assays
us
discrimination concentration limit between L-Cys and D-Cys was approximately 5 mM.
M
The fluorescence of perazamacrocycle 132 (Figure 94) [224], was quenched by Cu2+ through the formation of complex 132-Cu2+ with 1:1 stoichiometry and an association constant of 1.25×106 M-1. The
d
enantioselectivity of 132-Cu2+ toward Phe, Ala, Val and Pro was investigated due to the strong
te
association of Cu2+ with AAs that displaced 132 in the 132-Cu2+ complex [225]. Taking the recognition
Ac ce p
of Phe enantiomers as an example, both D-phe and L-phe induced apparent fluorescent enhancement responses by titrating the enantiomers of Phe to a mixture of 132 and Cu2+ (molar ratio of 132/Cu2+ was 1/2), whereas D-Phe was more effective than L-phe. The fluorescence of 132-Cu2+ (10 μM/10 μM) was enhanced 14.9-fold in the presence of D-phe (0.1 mM). Aswathy and Sony recently reported fluorescein (133)-(β-cyclodextrin)-Au NP assembly (Figure 95) [226] for FRET-based chiroselective turn-on sensing of Trp, Phe, and Tyr. 133 binds to the βcyclodextrin cavity with Ka=360 M−1 in the 133-(β-cyclodextrin)-Au NP assembly. FRET occurred from donor 133 to Au NP acceptor, which resulted in fluorescence quenching of 133 at 520 nm. 133-(βcyclodextrin)-Au NP assembly displayed high enantioselectivity to enantiomers of Trp, Phe, and Tyr. Upon addition of L-Trp, L-Phe, and L-Tyr to the assembly, the intensity of 133 increased in the 56 Page 56 of 184
Edited May 11
following order: L-Trp ＞ L-Phe ＞ L-Tyr. The FRET effect was inhibited because of the favored interaction of the phenyl ring with the β-cyclodextrin receptor, which expelled 133 from the βcyclodextrin cavity.
ip t
Insert Figures 94-95 Herein
us
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7. Pattern Recognition
The development of fluorescent/luminescence receptors for AAs with high selectivity is still a
an
challenge because of the structural similarity of the various AAs. Selectivity was achieved mainly by using receptors that could recognize a certain functional group of an AA side chain (e.g., imidazole of
M
His, thiol of Cys or carboxylate of Asp or Glu). On the other hand, a single-sensor approach would have trouble distinguishing simple, nonfunctionalized AAs, such as Ala or Val, due to the lack of sufficiently
d
specific receptors. An array-based approach would be suitable for achieving the required selectivity.
te
Pattern recognition is a very powerful tool because it can analyze a wide range of chemical
Ac ce p
structures and complex mixtures [227-231]. The IDAs approach, which relies on competition between an indicator and the analyte of interest for the binding site of a receptor, has been used to quantify a range of analytes, in which the receptor should have specific selectivity and sensitivity toward the analytes [232]. For the IDAs in the pattern recognition methods, a synthetic receptor does not need to exhibit specific or very selective binding to a target analyte. Instead, the receptors in the array only need to bind differently to various analytes, thereby creating a range of patterns for the analytes. Nevertheless, some degree of rational design is still effective for differential receptors because the receptors must have some affinity to the analytes, as well as some selectivity. The multi-analyte differential analyses with discrimination based on the molecular structure (chemoselectivity) and absolute configuration (enantioselectivity) was achieved using a pattern 57 Page 57 of 184
Edited May 11
recognition technique. The use of the less expensive and more commonly used instruments, such as UVVis spectroscopy [233-235] or fluorescence spectroscopy allows easy conversion to high-throughput screening (HTS) methods through the incorporation of a microplate reader, which allows rapid analysis of multiple samples.
ip t
UV-Vis spectra have been utilized to pattern recognition of natural AAs. For instance, in 2005, Buryak and Severin reported that the 20 natural AAs could be discriminated using an IDA-based assay
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with high fidelity by UV-Vis spectra in combination with multivariate analysis (Figure 96) [236]. The
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UV-Vis response at 750 nm of an IDA composed of complex 134 (50 μM) and 135 (100 μM) was used to classify the AAs (750 μM) into a high-affinity group (Group I) consisting of His, Cys, methionine
an
(Met), Asp and asparagine (Asn), for which almost quantitative replacement of indicator 135 from complex 134 was observed (∆A(750 nm) < 0.06), and a low-affinity group (Group II) consisting of the
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remaining 15 AAs showing partial replacement of the dye (0.55 > ∆A(750 nm) > 0.06). Each member of Group I was analyzed using the four IDAs (two indicators, 136 and 137, and two different pH values),
d
whereas each member of Group II was analyzed using five IDAs (indicator 135 at five different pH
te
values). All analyses were repeated 12 times with all data being collected in a highly parallel manner
Ac ce p
using a microplate reader. Using the pattern recognition approach, only Val and isoleucine (IIe) showed some overlap; the cyclic AA, Pro, was well separated from the rest; the hydroxy AAs, such as Ser and Thr, and the aromatic AAs, such as Phe, Tyr, and Trp, were positioned in proximity to each other; the closely related AAs, such as Leu and IIe, are clearly distinguishable, which would be very difficult to achieve using a classical one sensor-one analyte approach. As another example, in 2006, Anslyn et al. reported that a series of enantioselective IDAs, Cu2+ complexes of bidentate N-donor ligands 138-140 and 141-143, could be used as receptors and indicators, respectively (Figure 97) [237]. The selected indicators undergo large red shifts in their absorbance spectra upon metal coordination. The absorption and visual color of the indicators were recovered after adding the AAs analytes. The recovery was dependent on the ratio of AAs bound to the free indicator 58 Page 58 of 184
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and the stability of the receptor-AA complex. A two-dimensional plot (PC1 axis and PC2 axis) was given that could be used to identify the diagnostic patterns present in the array. All the AAs investigated were ordered chemoselectively along PC1, with scores inversely related to the sequence of the affinities for the receptor complexes. The chiral information is expressed predominantly along PC2, with negative
ip t
scores for D-AAs and positive scores for L-AAs. The aliphatic AAs (Leu, Val, Ile), which vary only by the side chain methylene groups, were separated clearly.
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A literature survey reveals that less attention was paid to the pattern recognition of AAs by the
us
fluorescence/luminescence metal-organic systems. The fluorescence ratiometric probes of BSA-AuNCsmetal (Figure 98) [238] provide a sensory method for the identification of AAs. BSA-AuNCs exhibited
an
dual emissions: blue emission at 425 nm from the oxides of BSA and red emission at 635 nm from the AuNCs. The BSA-AuNCs can interact effectively with many metal ions, such as Ni2+, Pb2+, Zn2+ and
M
Cd2+, due to the large amount of residual amino, carboxylic and mercapto groups, and disulfide bridges at the peptide chains of BSA. The fluorescence responses of BSA-AuNCs to metal ions were quite
d
specific: Ni2+ quenched both the fluorescence intensities at 425 nm and 635 nm, with a quenching
te
efficiency of emission at 425 nm and 635 nm of 70% and 82%, respectively. Pb2+ quenched the
Ac ce p
emission of the oxides of BSA significantly and the red emission changed slightly. In contrast, Zn2+ and Cd2+ enhanced the emission at 635 nm with a slight blueshift to 630 nm, whereas the emission at 425 nm showed a slight change. The metal ion-modulated BSA-AuNCs showed a ratiometric response to specific AAs. BSA-AuNCs-Ni2+ showed ratiometric fluorescence response after the addition of His with the emission at 635 nm enhanced significantly and the emission at 425 nm from the oxides of BSA changed only slightly. The fluorescence ratio of BSA-AuNCs-Pb2+ between 425 nm and 635 nm was increased by the presence of Asp. The ratiometric fluorescence response of BSA-AuNCs-Zn2+ and BSA-AuNCs-Cd2+ was observed in the presence of Cys and Asp. BSA-AuNCs-Ni2+, as an example, is quite sensitive to His but other AAs also affect the ratio of the dual emissions intensity because they can also coordinate with Ni2+, even though the effect is much weaker than His. On the other hand, the 59 Page 59 of 184
Edited May 11
responses of some AAs, such as Cys, Ala and Gln, are similar to each other. This makes it impossible to discriminate the various AAs using a single probe. Therefore, BSA-AuNCs-Ni2+, BSA-AuNCs-Pb2+, BSA-AuNCs-Zn2+ and BSA-AuNCs-Cd2+ were used as a fluorescence ratiometric sensor array to identify the various AAs by easy recognition of the signal patterns of the ratiometric fluorescence. The
ip t
addition of AAs (100 mM) resulted in a variety of fluorescence ratiometric responses. For example, Ala could not be identified from Cys in the BSA-AuNCs-Ni2+ system because they exhibit similar
cr
fluorescence responses but have different patterns in the array. Ala does not affect the ratio of BSA-
us
AuNCs-Cd2+ and BSA-AuNCs-Zn2+ in this sensor array, and is different from Cys. Therefore, Ala and Cys can be discriminated easily by the array, whereas it is impossible through a single probe. Other AAs
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also have their distinct responses, and these responses are expected to identify a range of AAs as a
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fingerprint.
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Ac ce p
8. Conclusions
d
Insert Figure 96-98 Herein
Metal-organic fluorescent/luminescent systems of different types that sense AAs have been devised and the recognition mechanisms of these systems have been studied in detail in the recent past. Among them, it is still a challenge to both selectively and sensitively discriminate AAs, owing to the similarity in the structure and reactivity of some AAs. Although additional coordination with other groups in the AA’s side chains, such as His and Phe, etc., has sometimes resulted in some preferential coordination, better reporters are still rare. In this case, pattern recognition is a very powerful tool because it can analyze diverse chemical structures and complex mixtures. The discrimination of AAs in stereo environments is very important, particularly in biological environments because D-AAs and L-AAs have
very
different
pharmacological
properties
and
bioactive
effects.
The
use
of
60 Page 60 of 184
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fluorescent/luminescent metal-organic systems for chiral and pattern recognition of AAs is still in its infancy. Significant progress has been made in chemosensor or chemodosimeters for AAs, such as His and Cys, over the past fifteen years. On the other hand, fluorescent/luminescent chemosensors or
ip t
chemodosimeters for the specific detection of Gly (glycine), Lys (lysine), Met, IIe, Leu, etc., based on metal-organic systems, have not been reported. Therefore, considerable research will be needed to
cr
develop better chemosensors or chemodosimeters for the detection of these AAs.
us
There is much research needed in order to develop better sensing systems for the detection of natural AAs in vitro and in vivo applications. For example, the most involved recognition is employed
an
successfully in organic solvents but not water. This confines these sensors to be used for recognition in biological applications; most fluorescent/luminescent detectors for AAs are based on the measurements
M
at a single wavelength, which might be affected by variations in the sample environment. In contrast, ratiometric fluorescent probes allow measurements of the emission intensities at two wavelengths,
d
which should provide a built-in correction for environmental effects. Moreover, a NIR optical response
te
(e.g., 700 to 900 nm) is ideal for therapeutic applications and suitable for use as tags or stains for bio-
Ac ce p
imaging. In addition, it offers additional advantages over the visible optical response, such as lower interference of auto-fluorescence from endogenous chromophores and deeper penetration of tissues. The development of fluorescent/luminescent probes, based on metal-organic systems is progressing gradually, so we are convinced that more selective, more specific and more practical probes for natural AAs could be designed in the not-too-distant future.
ACKNOWLEDGMENT
This work was financially supported by National Natural Science Foundation of China (Grant No. 31360020), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State 61 Page 61 of 184
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Education Ministry ([2014]1985), Guangxi Natural Science Foundation (No. 2014GXNSFCA118003), Scientific Research Foundation of Guangxi University (Grant No. XGZ130080 and XGZ130081), and grants funded by Opening Project of Guangxi Key Laboratory of Petrochemical Resource Processing and Process Intensification Technology (No. 2013K002) as well as Foundation for Fostering Talents of
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Department of Chemistry & Chemical Engineering, Guangxi University (Grant No. 2013102).
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FIGURE CAPTIONS
M
Table 1. Summary of fluorescent/luminescent amino acid sensors based on organic-metal complexes
nanoparticles/nanoclusters
d
Table 2. Summary of fluorescent/luminescent amino acid sensors based on hybrid organic-metal
te
Table 3. Summary of chiral recognition of AAs using fluorescent/luminescent sensors
Ac ce p
Figure 1. Chemical structures of compound 1 [38] and zinc complexe of 2 [39]. Figure 2. Chemical structures of compounds/zinc complexes of 3-7 [40-42]. Figure 3. Chemical structures of Zn(8) and Zn(9) [43]. Figure 4. Chemical structures of 10-12 [44]. Figure 5. Proposed binding mechanism of 13 and L-His [45]. Figure 6. Chemical structure of (Cu2+)2(14) [46] and 15 [47] and the reaction of (Cu2+)2(14) with Cys and His. Figure 7. The proposed binding mechanism of [Ir(16)]+ with His [48]. Figure 8. Chemical structures of 17, 18, 19 and time-dependent reaction of 17 with Cys [49]. Figure 9. Chemical structures of 20, 20-Au+, 21 and proposed binding mechanism of 20-Au+ with Cys 74 Page 74 of 184
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[50]. Figure 10. Chemical structures of Ce(22) [51] and 23 [53]. Figure 11. Chemical structure of 24 and the reaction mechanism of 24 with Ag+, Fe3+, and Cys [54]. Figure 12. Chemical structure of 25 [55].
Figure 14. Proposed mechanism for response of Zn(28) to Cys [58].
cr
Figure 15. Proposed mechanism for response of Zn(29) to Cys and His [59].
ip t
Figure 13. Chemical structures of Zn(26) [56], 27 [57], 30 [60], 31 [62].
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Figure 16. Chemical structures of 32 and 33 [66]. Figure 17. Proposed mechanism for response of 34-Cu2+ to Cys [6].
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Figure 18. Proposed mechanism for response of 35-Cu2+ with Cys and His [67]. Figure 19. Chemical structures of 36, rhodamine B, and schematic illustration of Cys detection [68].
M
Figure 20. Chemical structures of 37 [69], 38 [70], 37-Cu2+ and 38-Cu2+. Figure 21. Chemical structures of 39, 39-Cu2+ [71] and 40 [72].
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Figure 22. Chemical structures of 41, 42-Cu2+ and 42 [73].
te
Figure 23. Chemical structures of 43 and 43-Cu2+ [74].
Ac ce p
Figure 24. Chemical structures of 44 [75] and 45 [76]. Figure 25. Chemical structures of 46 [77], 47 [78], and proposed sensing mechanisms for thiols. Figure 26. Chemical structures of 48 and 48-Hg2+ [79]. Figure 27. Chemical structures of 49 and 49-Hg2+ [80]. Figure 28. Chemical structures of 50 and 50-Hg2+ [81]. Figure 29. Schematic illustration of Hg2+ induced aggregation of 51 [82], 52 [83] and aggregate dissociation in the presence of Cys. Figure 30. Schematic illustration of Cys detection based on reduced graphene oxide (rGO)–53-Hg2+ ensemble [84]. Figure 31. Chemical structures of 54 [85] and 55 [86]. 75 Page 75 of 184
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Figure 32. Chemical structures of 56, 56-Cd2+ and proposed sensing mechanism of 56-Cd2+ for Cys [87]. Figure 33. Chemical structures of 57 and 57-Al3+ [88]. Figure 34. Reaction mechanism of 58, 59 and 60 with amino acids (AAs) [89]. Figure 35. Reaction of 61 with Cys [90].
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Figure 36. Chemical structures of 62, 63 and reaction mechanism of 63 with Cys and Hcy [92]. Figure 37. Chemical structures of 64-67 [93].
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Figure 38. Chemical structures of 68 [94], 69 and reaction mechanism of 69 with Cys and Hcy [95].
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Figure 39. Cys/Hcy sensing mechanism of 70 [96]. Figure 40. Cys/Hcy sensing mechanism of 71 [97].
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Figure 41. Chemical structures of 72, 73 and Cys/Hcy sensing mechanism of 72 [98]. Figure 42. Schematic illustration of reaction of 74 with Cys/Hcy and Trp [100].
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Figure 43. Reaction of 75 with Cys yielding 76 [101].
Hcy [102].
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Figure 44. Chemical structures of 77, 78, 79 and schematic illustration of reaction of 77 with Cys and
te
Figure 45. Proposed reaction mechanism of 80 with thiols [31].
Ac ce p
Figure 46. The proposed reaction of 81 with sulfhydryl-containing AAs/peptides [105]. Figure 47. Chemical structures of 82, 83 and thiol sensing mechanism of 82 [106]. Figure 48. Chemical structures of 84, 85 and thiol sensing mechanism of 84 [107]. Figure 49. Schematic illustration of reaction of 86 with Cys and Hcy [108]. Figure 50. Reaction mechanisms of 87-90 with Cys and Hcy [109]. Figure 51. Chemical structure of 91 [110]. Figure 52. Schematic illustration of the detection mechanism of thiol using 92-Cu2+ in aqueous media [111]. Figure 53. Schematic illustration of the detection mechanism of thiol using 94-Cu2+ in aqueous media [112]. 76 Page 76 of 184
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Figure 54. Principle of a fluorescence assay for AAs using Cu2+ complexes of 96-99 [113-115, 117]. Figure 55. Chemical structure of 100, reaction mechanisms of 100-Cu2+ for Cys and 100-Ni2+ for His/Trp [118]. Figure 56. Chemical structures of 101 [119], 102 [119], 103 [120] and reaction mechanisms of 101-
ip t
Cu2+ and 102-Cu2+ with AAs. Figure 57. Chemical structure of 104 and proposed sensing mechanism of 104-Cu2+ with His [121].
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Figure 58. Schematic illustration of the 105/DNA-1/metal ion-based AA sensor [122].
us
Figure 59. Schematic illustration of His detection using DNA-2/106/Cu2+-based ensemble system [123]. Figure 60. Schematic illustration of DNA-3/Cu2+/107 ensemble with His and Cys [124].
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Figure 61. Schematic illustration of the detection mechanism of biothiols using Tb3+/DNA-4/Hg2+ ensemble [125].
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Figure 62. Schematic illustration of Cys detection using DNA-5/108/Hg2+-based ensemble [126]. Figure 63. Schematic illustration of Cys and GSH detection using DNA-6/Hg2+-based ensemble [127].
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Figure 64. Schematic illustration of bithiols detection using DNA-7/111/Hg2+-based ensemble [128].
te
Figure 65. Schematic representation of thiols detection based on GO/112/DNA-8 assembly [129].
Ac ce p
Figure 66. Chemical structures of 113 [130], 114 and 115 [131]. Figure 67. Schematic representation of Cys detection based on GO and silver-specific DNA-9 and DNA-10 [132].
Figure 68. Schematic representation of Cys detection based on GO/DNA-11 [133] and GO/DNA-12 [134].
Figure 69. Schematic illustration of Cys detection based on Tb3+/DNA-4/DNA-13/Ag+ sensing system [135]. Figure 70. Chemical structure of 116 [136]. Figure 71. Schematic illustration of reaction of 117 with Cys and Hcy [32]. Figure 72. Schematic illustration of reaction of 118 with Cys and Hcy [138]. 77 Page 77 of 184
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Figure 73. Schematic illustration of Cys detection based on metal–organic framework [139]. Figure 74. Schematic representations of the photochemical ring opening and closing of Au-SP in the absence and in the presence of AAs [144-145]. Figure 75. Schematic illustration of Cys detection based on Au NPs/120 system [157].
ip t
Figure 76. Schematic illustration of His detection based on Ni2+-modified Au NCs [158]. Figure 77. Schematic illustration of thiols detection based on 121/Ag NPs/carbonaceous nanospheres
cr
(C NPs) hybrid spheres [159].
us
Figure 78. Schematic illustration of His detection based on Hcy-capped CdTe quantum dots (QDs) [160].
an
Figure 79. Schematic illustration of AAs detection based on Tyr-functionalized CuInS2 QDs [163]. Figure 80. Schematic illustration of His detection based on dopamine-functionalized CdTe QDs [164].
M
Figure 81. Schematic illustration of His detection based on CdTe/CdS QDs-Phen complex [165]. Figure 82. Schematic illustration of thiols detection via inhibition of electron transfer between
d
CdTe/CdS QDs and TiO2 NPs [166].
Ac ce p
template [170].
te
Figure 83. Fluorescence response pattern of Ag NCs to thiols depends on the nature of the DNA
Figure 84. Schematic illustration of biothiols detection based on DNA-25/DNA-26/Cu NCs [171]. Figure 85. Schematic illustration of the detection mechanism of Cys using 122-stabilized Au NP [177]. Figure 86. Schematic illustration of the detection mechanism of Asp and Glu using 123-Au NPs composites [178].
Figure 87. Schematic illustration of the detection mechanism of thiols using BSA-stabilized Au NCs [179]. Figure 88. Chemical structures of 124 [180], 125 and proposed sensing mechanism of thiols using 125capped Ag NCs [183]. Figure 89. Schematic illustration of the detection mechanism of Cys and Hcy using HSA-stabilized 78 Page 78 of 184
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Au/Ag NCs [184]. Figure 90. Chemical structures of Cu-(R)-126, Cu-(S)-126, and 127 [217]. Figure 91. Chemical structures of the dansylated cyclodextrin derivatives 126, 128-130 [219]. Figure 92. Reaction mechanisms of 131-Cu+ and 131-Cu2+ for α-AAs [221].
ip t
Figure 93. Schematic illustration of L-/D-Cys detection based on D-Cys (or L-Cys) modified CdTe@CdS QDs [222].
cr
Figure 94. Chemical structure of complex 132-Cu2+ [224].
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Figure 95. Schematic illustration of AAs detection based on 133-(β-cyclodextrin)-AuNP assembly [226].
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Figure 96. Colorimetric identification of 20 natural AAs using IDA arrays composed of receptor 134 and the indicators 135-137 at different pHs [236].
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Figure 97. Ligands 138-140 and indicators 141-143 used to construct sensor array [237].
Ac ce p
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BSA-Au NCs-metal [238].
d
Figure 98. Schematic illustration of AAs identification based on fluorescence ratiometric probes of
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Table(s)
λex/λem (nm)
Specificity
Condition
Detection limit
Ref.
1–Zn2+
–/413
Trp
dioxane/H2O (4:1, v/v), pH 6.8
–
38
2
347/454
His
MeOH/H2O (6:4, v/v), pH 6.8
0.134 µM
39
3–Zn2+
370/430
–
–
–
40
4–Zn2+
398/510
–
–
–
41
2+
350/383
–
–
–
42
8–Zn2+
320/525
Arg
HEPES buffer, pH 7.4
2.05 µM
43
10–Zn2+
343/400
His
HEPES with 1% THF, pH 7.35
–
44
13
298/352
His
HEPES buffer, pH 7.35
–
45
14–Cu2+
350/552
His, Cys
HEPES buffer, pH 7.4
–
46
15–Cu2+
457/476,537
His
EtOH/HEPES buffer (6:4, v/v), pH 7.2
5 µM
47
[Ir(16)]+
350/505
His
PBS buffer
–
48
17
DMF/HEPES buffer (9:1, v/v), pH 7.0
1.26 µM
49
MeOH/H2O (1:99, v/v)
0.1 µM
50
DMF/H2O (7:3, v/v), pH 5.0–9.0
37.4 µM
51
cr
us
6–Zn
ip t
Complex
an
Table 1. Summary of fluorescent/luminescent amino acid sensors based on organic-metal complexes
Cys
500/560
Cys
Ce(22)
350/470
Trp
23–Al3+
390/470
His
HEPES buffer, pH 7.7
0.3 µM
53
24–Ag+
344/377,470
Cys
EtOH/H2O (1:9, v/v)
–
54
24–Fe3+
344/377,470
Cys
EtOH/H2O (1:9, v/v)
–
54
25
423/657
His
Tris/HCl buffer, pH 8.0
2 µM
55
26–Zn2+
320/440
–
–
–
56
27–Zn2+
320/444
–
–
–
57
2+
390/454
Cys
MeOH/HEPES buffer (2:1, v/v), pH 7.4
392(±23) ppb
58
28–Zn2+
390/454
biological thiol
reduced blood serum
846 ppb
58
390/454
Cys+His
EtOH/HEPES buffer (2:1, v/v), pH 7.4
–
59
360/495
His
MeOH
0.33 ppm
60
360/535
Cys
MeOH
0.42 ppm
60
30-Co2+
360/535
–
–
–
60
30-Mn2+
360/535
–
–
–
60
30-Ni2+
360/535
–
–
–
60
2+
350/550
His
CH3CN/HEPES buffer (1:1, v/v), pH 7.4
–
62
[Cu2(32)]4+/33
–/540
His
HEPES buffer, pH 7
–
66
34-Cu2+
670/850
Cys
DMF/human plasma
4.07 µM/4.37 µM
6
29–Zn2+ 30–Zn2+ 30-Cu2+
31-Zn
ed
ce pt
28–Zn
Ac
20–Au
M
450/504 +
Page 179 of 184
330/550
Cys/His
HEPES buffer, pH 7.4
–/–
67
36-Cu2+
560/583
Cys
EtOH/Tris-HCl buffer (4:6, v/v), pH 7.1
0.14 µM
68
37-Cu2+
410/500
His
HEPES with 0.5% DMSO, pH 7.4
3.1 µM
69
38-Cu2+
–/480
His
CH3CN/HEPES buffer (1:5, v/v), pH 7.4
–
70
39-Cu2+
496/502
Cys/Hcy
CH3CN/HEPES buffer (1:1, v/v), pH 7.4
0.17/0.25 µM
71
40-Cu2+
325/434,494
Cys
DMSO/HEPES buffer (1:9, v/v), pH 7.4
0.541 µM
72
42-Cu2+
305/482
Cys/Hcy/GSH
CH3CN/HEPES buffer (1:5, v/v), pH 7.4
–/–/–
73
43-Cu2+
418/541
Cys/Hcy/GSH
EtOH/HEPES buffer (9:1, v/v), pH 7.4
0.42/0.105/4.34 µM
74
44-Ag+
285/315,445
Cys
MeOH
514 ppb
75
45-Ag+
280/390
–
–
–
76
46-Hg2+
–/678
thiol AAs
CH3CN/H2O (2:1, v/v)
–
77
47-Hg2+
630/664
Cys
EtOH/H2O (3:7, v/v)
36.7 nM
78
48-Hg2+
324/436
Cys
HEPES with 1% DMSO, pH 7.4
9.6×10−11 M
79
49-Hg2+
488/520
Cys
CH3CN/H2O
1.60×10−8 M
80
50-Hg2+
350/401
Cys
DMSO/H2O (1:9, v/v)
–
81
51-Hg2+
484/532
Cys
DMF/H2O (9:1, v/v)
9.6 nM
82
52-Hg2+
562/591
Cys
THF/H2O (2:1, v/v)
91.3 nM
83
rGO–53-Hg2+
490/540
–
–
–
84
54-Hg2+
500/582
L-pro
MeCN/Tris-HCl buffer (1:1, v/v), pH 7.2
–
85
55–Hg2+
330/512
19 α-AAs
aqueous solution, pH 6.5
–
86
56–Cd2+
380/456
Cys
MeOH
58 ppb
87
57-Al3+
500/579
Arg
MeOH/Tris-HCl buffer (9:1, v/v), pH 7.0
2.3 µM
88
58
467/
sulfhydryl AAs
DMF-phosphate buffer (1:1, v/v), pH 7.0
–
89
59
467/598
sulfhydryl AAs
DMF-phosphate buffer (1:1, v/v), pH 7.0
–
89
60
467/–
sulfhydryl AAs
DMF-phosphate buffer (1:1, v/v), pH 7.0
–
89
61
408/504,533
Cys
CH3CN/Tris (1:1, v/v) with 5% DMF, pH 7.2
–
90
365/560
–
–
–
92
365/510
Cys/Hcy
CH3CN/H2O (4:1, v/v), pH 7.2
–
92
360/615
Hcy
DMSO/HEPES buffer (9:1, v/v), pH 7.2
–
94
69
360/547,586
Cys/Hcy
DMSO/HEPES buffer (9:1, v/v), pH 7.2
–
95
70
–/572
Cys/Hcy
HEPES buffer, pH 7.2
–
96
71
365/545
Cys/Hcy
PBS buffer, pH 7.4
–
97
72
360/590
Cys/Hcy
CH3CN/PBS buffer (3:1, v/v), pH 8.1
–/0.13 mM
98
74
323/606
Hcy+Cys/Trp
CH3CN/HEPES buffer (1:1, v/v), pH 7.4
–
100
75
358/587
thiol AAs
DMF/HEPES buffer (4:1, v/v), pH 7.2
–
101
63 68
cr
us
an M
ed
ce pt
Ac
62
ip t
35-Cu2+
Page 180 of 184
–/603
Cys/Hcy
CH3CN/H2O (4:1, v/v), pH 7.2 (living cells)
– (–)
102
80
430/564
Hcy/Cys/Trp
CH3CN/HEPES buffer (1:1, v/v), pH 7.5
36.9/67.6/24 nM
31
81
467/595
sulfhydryl AAs
DMF/H2O (1:1, v/v), pH 7.4
–
105
82
455/598
thiols
CH3CN/H2O (4:1, v/v), pH 7.4
–
106
84
456/612
Cys/GSH
HEPES buffer, pH 7.0
20.1/19.8 nM
107
86
460/720
Cys/Hcy
DMSO/HEPES buffer (9:1, v/v)
1.41/1.19 μM
108
87
450/605
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
0.5/0.4 μM
109
88
450/607
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
0.4/0.2 μM
109
89
450/612
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
0.2/0.5 μM
109
90
482/622
Cys/Hcy
CH3CN/Tris buffer (10:1, v/v), pH 7.2
1.0/0.3 μM
109
91
439/605
Cys /Hcy/GSH
HEPES buffer, pH 7.5
229/227/242 nM
110
92-Cu2+
479/514
Cys /Hcy/GSH
PBS buffer with 1% DMSO, pH 7.4
–/–/10 nM
111
94-Cu2+
485/515
Cys/Hcy/GSH
HEPES buffer with 1% CH3CN, pH 7.4
9 μM/–/–
112
96-Cu2+
335/453
α-AAs (His)
EtOH/H2O
– (2.1 ppm)
113
97-Cu2+
431/~505
α-AAs (Gly)
EtOH/H2O
– (2.0 ppm)
114
98-Cu2+
355/~405
α-AAs
EtOH/H2O
–
115
99-Cu2+
410/460,485
α-AAs (Gly)
THF
–(7.7 nM)
117
100-Cu2+
367/429
Cys
THF
0.5 μM
118
100-Ni2+
367/429
His/Trp
THF
–
118
101-Cu2+
310/410
–
–
–
119
102-Cu2+
310/410
–
–
–
119
103-Cu2+
400/528
Cys/GSH
aqueous solution
45/40 nM
120
104-Cu2+
320/481
His
DMSO/H2O
–
121
DNA-1/105/Cu2+
490/540
His
Tris-HCl buffer, pH 7.0/diluted urine
10 nM/–
122
DNA-1/105/Hg2+
490/540
Cys
Tris-HCl buffer, pH 7.0
5.1 nM
122
DNA-2/106/Cu2+
360/575
His
Tris-HCl buffer, pH 7.0
1 μM
123
cr
us
an M
ed
ce pt
Ac
ip t
77
DNA-3/107/Cu2+
399/608
His
HEPES buffer, pH 7.0
3 nM
124
Tb3+/DNA-4/Hg2+
290/546
Cys/Hcy/GSH
Tris-HAc buffer, pH 7.9
0.5 μM/–/–
125
DNA-5/108/Hg2+
360/583
Cys/GSH
Tris-HCl buffer, pH 7.0
5 nM/–
126
DNA-6/109/110
480/518
Cys/GSH
MOPS buffer, pH 7.45
4.2/4.1 nM
127
111/DNA-7/Hg2+
440/485
Cys/GSH
Tris-HCl buffer, pH 7.2
8.4/13.9 nM
128
GO/112/DNA-8
455/605
Cys/GSH
Tris-HCl buffer, pH 7.0
6.20/4.60 nM
129
113−Hg2+−T
350/420,630
Cys
PBS buffer, pH 7.4
60 μM
130
114-Ag+
333/456
Cys
dioxane
90 nM
131
115-Ag+
333/416,560
Cys
dioxane
150 nM
131
Page 181 of 184
480/538.2
Cys
HEPES buffer, pH 7.0
44 nM
132
GO/DNA-11/Ag+
493/520
Cys
HEPES buffer, pH 7.4/human serum
–/5 nM
133
GO/DNA-12/Ag+
480/520
Cys
Tris-HCl buffer, pH 8.0/human urine
0.1 μM/–
134
Tb3+/DNA/Ag+
290/546
Cys
Tris-HAc buffer, pH 7.9
–
135
116–Co2+
352/416
Cys
PBS buffer, pH 7.4
0.16 μM
136
117
365/567
Cys/Hcy
HEPES buffer, pH 7.2 (living cell)
2.4/1.2 mM (–/–)
32
118
–/564
Cys/Hcy
PBS buffer, pH 7.0
–
138
119-ZIF-90
–/~430
Cys/H2S
–
25 μM/–
139
Ac
ce pt
ed
M
an
us
cr
ip t
GO/DNA 9,10/Ag+
Page 182 of 184
Table(s)
Table 2. Summary of fluorescent/luminescent amino acid sensors based on hybrid organic-metal nanoparticles/nanoclusters Particle size
λex/λem (nm)
Specificity
Condition
Detection limit
Ref.
CdSe/ZnS QDs
3.1 nm
388/565
L-Cys
phosphate buffer, pH 7.8
3.8 nM
150
CdS QDs
4–6 nm
370/540
Cys
PBS buffer, pH 9
5.4 nM
151
120/Au NPs
24 nm
680/747
Cys/Hcy/GSH
PBS buffer, pH 7.4
BSA-Au NCs-Ni2+
1 nm
480/605
His
121/Ag NPs/C NPs
~100 nm
–/~515
Hcy–CdTe QDs
2.93 nm
CuInS2 QDs
ip t
NPs/NCs
157
Tris-HCl buffer, pH 7.0
30 nM
158
Cys/GSH etc.
sodium acetate buffer, pH 5.0
0.2 μM/20 nM
159
360/574
His
Tris-HCl buffer, pH 9.0
0.3 μM
160
–
–/660
Cys/GSH/His/Thr
PBS buffer, pH 7.0
0.5/–/0.7/2.0 μM
163
DA–CdTe QDs
2 nm
400/568
L-His
Tris-HCl buffer, pH 8.6
0.5 μM
164
CdTe/CdS QDs
2 nm
370/545
Cys/Hcy
Tris-HCl buffer, pH 7.4
0.78/0.67 μM
165
QDs–TiO2
–
–/580
Cys/Hcy/GSH
citrate buffer, pH 6.0
–/–/0.17 μM
166
DNA-14/Ag NCs
–
550/610
Cys/Hcy/GSH
PBS buffer, pH 7.4
4 nM/0.2 μM/4 nM
169
DNA-15/Ag NCs
–
–/615
Cys/Hcy/GSH
–
2.1/1.5/6.2 nM
170
DNA-CuNCs
–
340/580
Cys/Hcy/GSH
MOPS buffer, pH 7.5
2/5/2 mM
171
122-Au NPs
5.1±0.8 nm
370/420,450,475
Cys
aqueous solution
25 nM
177
123-Au NPs
13.8±1.5 nm
–/514
Asp/Glu
Pure water
32/57 nM
178
BSA-Au NCs
1 nm
360/660
Cys/Hcy/GSH
MOPS buffer, pH 7
8.3/14.9/9.4 nM
179
124-Ag NCs
–
510/615
Cys
PBS buffer, pH 7.0
20 nM
180
125-Ag NCs
2 nm
375/455
Cys/Hcy/GSH
boric acid–borax buffer, pH 8.2
42/47/380 nM
183
HSA-Au/Ag NCs
1.5±0.2 nm
510/620
Cys+HCy
PBS buffer, pH 7.0
15 nM
184
Ac
ce pt
ed
M
an
us
cr
10 nM/–/–
Page 183 of 184
Table(s)
Table 3. Summary of chiral recognition of AAs using fluorescent/luminescent sensors λex/λem (nm)
Specificity
KD/KL
FD/FL
Condition
Detection limit
Ref.
Cu-(S)-126
–/–
Pro/Phe/Trp
–/–/–
3.89/0.33/0.63
tetraborate buffer, pH=7.3
–/–/–
217
L-126
344/516
Pro/Val
–/–
2.778/0.618
borate buffer, pH=7.0
–/–
219
L-128
346/515
Pro/Val
–/–
1.757/0.563
borate buffer, pH=7.0
–/–
219
L-129
341/514
Pro/Val
–/–
1.782/0.488
borate buffer, pH=7.0
–/–
219
L-130
341/516
Pro/Val
–/–
3.788/0.585
borate buffer, pH=7.0
–/–
219
131-Cu+
230/359
Leu/Pro
–/–
–/–
EtOH
–/–
221
L-QDs-GNRs
400/720
Cys
–
2.57
Tris-HCl buffer, pH 6.6
0.8 nM
222
D-QDs-GNRs
400/720
Cys
–
–
Tris-HCl buffer, pH 6.6
0.8 nM
222
L-GSH–Ag NCs
350/440
L-Cys
–
–
PBS buffer, pH=7.4
3.4 nM
223
132-Cu2+
331/380
Phe/Ala/Val/Pro
–/–/–/–
–/–/–/–
MeOH/HEPES (1/1, v/v), pH=7.4
–/–/–/–
224
133-βCD-Au NP
440/520
Trp/Phe/Tyr
61.3/37/29.3
–/–/–
Tris-HCl buffer, pH 7.6
0.59/1.2/1.5 μM
226
Ac
ce pt
ed
M
an
us
cr
ip t
Complex or NPs
Page 184 of 184