Recent advances in cyclodextrins-based chiral-recognizing platforms

Trends in Analytical Chemistry 121 (2019) 115691

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Recent advances in cyclodextrins-based chiral-recognizing platforms Si-Ying Wang a, Le Li a, Yin Xiao b, **, Yong Wang a, * a

School of Science, Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin, 300072, PR China b School of Chemical Engineering and Technology, Tianjin Engineering Research Center of Functional Fine Chemicals, Tianjin University, Tianjin, 300072, PR China

a r t i c l e i n f o

a b s t r a c t

Article history: Available online 8 October 2019

Chirality is one of the basic attributes of nature. Generally, enantiomers exhibit different or even entirely opposite metabolic, toxicological and pharmacological properties in organisms. Hence, chiral recognition is of great importance especially in areas of bioanalysis, pharmaceutics, biomedicines, etc. Cyclodextrins (CDs) are cyclic oligosaccharides with plenty of chiral centers, playing a crucial role in enantiomers discrimination. Due to the unique truncated cone shape structure including a hydrophobic inner cavity and a hydrophilic exterior, CDs are able to recognize optical stereoisomers through host-guest interaction. By far, a board range of analytical techniques has been developed based on CD derivatives for chiral recognition, such as electrochemistry, luminescence, nuclear magnetic resonance (NMR), etc. However, there are still very few reviews focusing on advances in CDs-based enantiomers discrimination techniques. Therefore, we present this review to summarize the recent advances in CDs-based chiral recognition techniques. Both the design strategies and the recognizing mechanisms that transform discriminating process into detectable signals are discussed in details. © 2019 Elsevier B.V. All rights reserved.

Keywords: Cyclodextrins Recognition Enantiomers Sensing Chiral discrimination

1. Introduction Thalidomide event was one of the largest miserable accidents of drug toxicity in human history [1]. Since 1960s, the scientific research community has laid tremendous emphasis on chirality especially in the area of biomedicines [2]. Actually, chirality is a widespread phenomenon in nature, acting as a critical part in the metabolism of organisms. Stemming from the lack of a plane of symmetry, a pair of chiral molecules, which can be called enantiomers, are the mirror images of each other but nonsuperimposable. They may have similar chemical and physical properties yet usually exhibit different biological effects on living systems due to specific interactions with the biomolecules participating in biochemical processes [2e6]. Therefore, it is essential to develop effective methods for enantiomer discrimination. Chiral recognition is not an easy work because of the extremely similar molecular configuration of optical isomers. Nevertheless, supramolecular chiral selectors have good

* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (Y. Wang).

(Y.

Xiao),

https://doi.org/10.1016/j.trac.2019.115691 0165-9936/© 2019 Elsevier B.V. All rights reserved.

[email protected]

performance on enantiomeric discrimination mainly by forming host-guest complexes with chiral guests [7,8]. Cyclodextrins (CDs) are a well-known family of structurally well-defined supramolecules, which act as crucial parts in chiral recognition platforms [9]. Native CDs are cyclic oligosaccharides consisting of six, seven or eight D-glucose units bonded via a-1,4glycosidic linkages, forming a cone structure [10e12]. The arrangement of atoms and groups contributes to the formation of unique stereochemical structures with a hydrophobic inner cavity and a hydrophilic exterior as complementary units (Fig. 1), and that is the primary reason why CDs are endowed with the property of selectively binding various guest molecules. Besides, functionalization of CD rims can expand the scope of CDs applications in both chiral recognition and separation applications by introducing multiple interactions such as hydrogen bonds, p-p interaction and dipole-dipole effects [13e15]. With regard to the chiral separation science, CDs play an extremely significant role in chromatography [16e19], including capillary electrophoresis [20,21], gas chromatography [22] and liquid chromatography [23]. A high amount of assays have been used up for the separation and quantification of chiral analytes, which is of great importance for food chemistry, clinical medicine, pharmaceutical industry in consideration of the special properties of enantiomers. And numerous works published

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Fig. 1. (A) Molecular structure of b-CD. (B) Schematic illustration of the hydrophobic and hydrophilic regions of an b-CD cylinder.

in this field lay a foundation for chiral recognizing area [9,14,24]. Meanwhile, comprehension understanding the recognition mechanisms is also the primary basis for chiral separation. Thus, it is essential to investigate interactions between CDs and enantiomers for establishing analytical methods. This review discusses about enantiospecific recognition techniques based on CDs and the corresponding chiral sensing mechanisms. To the best of our knowledge, there is very limited reviews summarizing the advances in chiral recognizing and sensing platforms based on CDs in the past five years by far. Diverse techniques have been utilized to transform the process of molecular interaction into detectable signal changes, such as electrochemistry, luminescence, nuclear magnetic resonance (NMR), and so on. According to the signal categories, this review summarizes the relevant researches on chiral sensing based on CDs materials and highlights the advantages of each method. More importantly, molecular interaction mechanisms are also discussed using specific host-guest complex examples. What's more, methods for diastereomers discrimination are also mentioned. For diastereomers, some chiral centers have opposite configurations. Although they are not mirror images of each other, they are optical isomers and have similar configurations. Hence, the discrimination of diastereomers by CDs is important for chiral recognition. We hope that this review could promote the understanding of enantioselectivity and provide elegant ideas for chiral sensing. 2. Chiral-recognizing platforms based on electric signals 2.1. Strategies based on carbon materials assisted chiral sensing As a ‘‘rising star’’ employed in electrochemistry with advantages of high surface area, abundant edge sites, high intrinsic mobility and good electrical conductivity, graphene family including zerodimensional graphene quantum dots (GQDs) [25,26], twodimensional graphene nanosheets (GNs) [27e31] and threedimensional network graphene [32], have aroused extensive interest. Graphene materials can function as CDs supports on electrode surface, and they can amplify electrochemical signals relying on their excellent electrical conductivity. Meanwhile, CDs can improve the water dispersivity of graphene and bring in enantiorecognition ability. For example, in the electrochemical enantioselective analysis of moxifloxacin hydrochloride (MOX) reported by Upadhyay et al. (Fig. 2A), the redox peak pairs of plane carbon paste electrode (CPE) exhibited in cyclic voltammetry were effectively increased by employing GNs-b-CD-CPE, compared with the current response of b-CD-CPE without GNs [28]. In the meantime, it is evidenced by differential pulse voltammogram that b-CD

contributes to the chiral discrimination efficiency. b-CD has 35 chiral centers, guaranteeing that diverse enantiomers can be included in their most compatible mode. MOX has two chiral centers in diazabicyclonoyl ring. The cyclic structure of S,S-MOX is located inside CD nanocavity, leading to a larger stability constant than R,R-MOX whose secondary amino group prefers to interact with the hydroxyls on CD rims. On the basis of CDs and graphene, researchers also introduce other materials to assist the design of sensing electrodes. Si et al. prepared CD functionalized reduced graphene oxide to coat glassy carbon electrode (GCE) and used methylene blue as the indicator for both qualitative and quantitative analyses of aromatic-free D- or L-tartaric acid [33]. Methylene blue can improve the sensitivity of enantiorecognition by amplifying the signal of redox peak in cyclic voltammetry. What's more, a graphene/diamond electrode with advantages of good stableness and regeneration was employed in fabricating CDs-based enantiomer recognition platforms [34]. Metal compositions, like platinum (Pt) and palladium (Pd) bimetal nanowires [35] or Pt nanoparticles [36], are good at increasing electrical conductivity and thus promise a sensitive response dur~ oz et al. ing the process of CD interacting with optical isomers. Mun combined both chiral magnetic-nanobiofluids (mNBFs) and nanocomposite graphene-paste electrode (NC-GPE) to resolve enantiomers, opening up a new research branch in CDs-based chiral sensing areas [37]. Carbon nanotubes (CNTs) are another attractive type of carbon material with porous nanostructure. Poly-L-arginine (PLA) can interact with multi-walled carbon nanotubes (MWCNTs) to form a poly porous cluster nanostructure [38]. Lei et al. developed a method based on coordination self-assembly of Cu2þ-modified bCD on poly-L-arginine/multi-walled carbon nanotubes (Cu-b-CD/ PLA/MWCNTs) to distinguish tryptophan (Trp) enantiomers. Cu2þ functions as a “gate” of the secondary rim of b-CD to impede the escape of the high-energy water from the hydrophobic cavum, playing an essential role in complexation process. Since the amino group of L-Trp is capable of binding with the high-energy water via H-bonds, L-Trp can be captured when entering CD cavity from the primary face. Meanwhile, the energy of water would be reduced and a stable state is reached. Yi et al. used core-shell heterostructure carbon nanotubes wrapped with reduced graphene oxide (CNTs@rGO) nanostructure to prepare a highly selective and sensitive electrochemical sensor based on CDs, as shown in Fig. 2B [39]. The electrode performance can be improved by the excellent merit of CNTs@rGO nanohybrids. CNTs core facilitates the electron transfer rate inside nanocomposites, and helps rGO nanosheets to overcome the shortcoming of generating agglomerates, guaranteeing the exposure of enough electrochemical active binding sites

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Fig. 2. (A) Schematic illustration of chiral recognition mechanism for MOX enantiomers (reprinted from Ref. [28] with permission from Elsevier). (B) Schematic illustration of chiral recognition mechanism for Phe enantiomers (reprinted from Ref. [39] with permission from ACS). (C) Schematic illustration of chiral recognition mechanism for AAAs enantiomers (reprinted from Ref. [47] with permission from RSC).

on rGO. Besides, this detection method also applied a novel dual signals strategy based on the competitive complexation with CDs between Rhodamine B (RhB) and phenylalanine (Phe) stereoisomers. The peak of RhB dropped dramatically after adding L-Phe, whereas there appeared a distinct peak of L-Phe. Reversely, this phenomenon was not observed in D-Phe analysis since D-Phe cannot take place of RhB to associate with CDs. Dual signal changes demonstrate unambiguous support for sensing and quantitatively determining L-Phe. Just like Yi et al. utilizing RhB to afford dual signals [39], researchers employed diverse strategies to improve electrical responses since the sensitivity is essential in CDs-based electrochemistry chiral recognition platforms. MWCNTs-ionic liquids (IL) nanocomposite has features of high active surface area and promising electronic transport, leading to increased current signals [40]. Furthermore, IL can turn MWCNTs into a homogeneous and uniform morphology. Song et al. designed a chiral recognition electrode modified by multilayer nanocomposite, including aminomodified b-CD (NH2-b-CD), gold-platinum core-shell microspheres (Au@Pts), polyethyleneimine (PEI) and MWCNTs [41]. It was found that the current difference between L-Trp and D-Trp was enhanced with the above substrate materials. Niu et al. immobilized ferrocene (Fc) onto MWCNTs through either p-p stacking or covalent bond to realize electrical signal response improvement [42]. Apart from graphene and CNTs, other carbon materials also play a vital role in CDs-based chiral recognizing platforms. Fu's group synthesized hollow carbon microspheres (HCMS) and then functionalized with gold nanoparticles (AuNPs) to afford AuNPs/HCMS

hybrids [43]. Thiol-b-CD (SH-b-CD) was thereafter assembled onto the hybrid materials based on the formation of “AueS” bonds to recognize and determine ascorbic acid (AA) and isoascorbic acid (IAA). In another work, they utilized fullerene (C60) that had richconjugated p-electrons to link eNH2 groups of L-cysteine (L-Cys) to form C60-L-Cys derivatives [44]. Amino groups of tyrosine (Tyr) can interact with CD hydroxyls or carboxyl groups of C60-L-Cys through hydrogen bonds. So C60-L-Cys and SH-b-CD that are bonded to porous Au@Pd bimetallic nanoparticles (Au@Pd) exhibit the same function for distinguishing stereoisomers of Tyr. The hydrogen-bond modes of D- or L-Tyr with the chiral interface are different because of the stereo-specificity caused by the different steric hindrance. Thus, more D-Tyr can combine with C60-L-Cys and SH-b-CD. Xiao et al. applied N-doped carbon dots and b-CD nanocomposites (N-CDots/b-CD) to establish a sensing platform for Trp enantiomers [45]. N-CDots increased the CD loading on GCE surface. N-CDots/b-CD formed a homogeneous and compact membrane, while only a small amount of pure CD electrodeposites on GCE, leaving the majority of electrode surface uncovered, which may result from CD's electron-insulating feature and weak adsorption ability. 2.2. Strategies based on carbon-free materials assisted chiral sensing Although some carbon-free materials do not own advantages like high surface area as graphene does, they may possess the structure of nanochannels that are capable of immobilizing CDs. Xie

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et al. designed a stable platform to distinguish L-Trp from D-Trp based on a b-CD-modified single nanochannel fabricated in the polyimide (PI) membrane [46]. Upon generating host-guest inclusion complexes, PI surface feature was tuned and therefore causing ionic current change of the nanochannel. Guo et al. decorated heptakis (6-deoxy-6-amino)-b-CD (7-NH2-b-CD) into a protein nanopore as recognition elements, which may provide a promising platform to study thermodynamics and kinetics of chiral multicomponent complex at single-molecule level [47]. Copper (II) ion that connected with CD amino groups is just like a plug valve to keep amino acids staying in the nanocavity, guaranteeing adequate registering time for chiral resolution, as presented in Fig. 2C. Based on this strategy, it was found that natural aromatic amino acids (AAAs) produced discernible current signal, whereas aliphatic amino acids did not match the CD cavity so no detectable current change was observed. For the studied six AAAs enantiomers, not just chiral recognition was achieved. Moreover, distinctive characteristic signals of each molecule were acquired by comprehensively analyzing the current blocking signals, blockage current Gaussian fitting curves and peak values of the dwell time, so that five AAAs enantiomers could be clearly identified. Metal-organic framework (MOF) is also a type of porous material with regular and orderly structure. Wu et al. firstly introduced b-CD into MOF molecular imprinting sensor for L-Phe detection with high-precision [48]. Nonspecific recognition caused by the rigid structures of MOF was effectively reduced on account of the remarkable performance of CDs in selective inclusion complexation. In addition, L-Cys was employed to functionalize the framework. As presented in Fig. 3, when the benzene ring of L-Phe is captured in CD cavity through strong hydrophobic effect, the other end of the analyte will be exposed and binded with charged groups of L-Cys via

complementary zwitterionic electrical interactions. However, the structure of D-Phe does not fit those binding sites. Several amino acids with similar configuration as well as some common ions were also checked. Results show that the sensor exhibits an ideal antiinterference ability. This double selective identification model is a good strategy to design chiral recognition platforms. The sensing process can be expressed as following: target molecules are oriented into regular arrangement by CD, leaving specialized functional groups to be “locked” precisely by the other selector. Deng et al. selected a g-CD MOF for discrimination of pinene enantiomers [49]. During the electrochemical process, enantiomer molecules first diffuse into nanochannels of g-CD MOF, and then interact with chiral framework discrepantly. Chitosan (CS) is a kind of natural polysaccharide applied for enantioselective discrimination, yet the insufficient stability of CS in aqueous solution limits its efficiency in enantiomer recognition. Efforts have been made to enhance the chiral discrimination efficiency of CS by introducing CDs. Zilberg et al. constructed a selective voltammetric electrode with the sensing layer composed of chitosan polyelectrolyte complexes with b-CD, and successfully applied the established analysis platform for determining atenolol enantiomers in human urine samples [50]. It is suggested in the research of Kong's group that H-bonds may play an essential role in synergistic effect of CD and CS [51]. Compared with its isomer, DTyr trends to combine with CS/Cu2-a-CD due to the stable intermolecular H-bonds. In contrast, L-Tyr can more easily penetrate into the 2-fold helical chiral structure of CS due to less steric hindrance, and then gets oxidized on the surface of GCE. Kong's group applied poly (L-glutamic acid) (P-L-Glu) that has similar chiral surface like CS to design sensing electrodes [52,53]. After modifying GCE with L-Glu by electropolymerization, CDs

Fig. 3. Schematic illustration of chiral recognition mechanism for Phe enantiomers (reprinted from Ref. [48] with permission from Springer).

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assembled onto P-L-Glu. Current signal difference was observed upon Trp enantiomers detection. It was found that temperature has a vital influence on the sensor's recognition efficiency, which might result from the variation of the hydrogen bonding strength. Chiral recognition relies on hydrogen bonds between Trp isomers and high-energy water molecules inside the CD cavity [53]. As temperature increased gradually, those intermolecular forces exhibited uneven power in the competition with H-bonds existing among high-energy water. It should be pointed out that the mechanism governing the temperature influence on stereoisomers discrimination is very complicated. H-bond is not the only changing factor during the temperature variation. Actually, the orientations, positions and conformations of CDs are all temperature-dependent. By the way, except for temperature, pH [54] and CDs type [55] also have impact on the detection capabilities of the CDs-based sensing platforms. As one of the most interesting electronic devices, organic fieldeffect transistors (OFETs) can provide an ideal sensing platform with advantages such as the compact integration, real-time analysis and rapid response [56,57]. Most resolution processes based on OFETs rely on the induced charge changing in the semiconductor layer caused by external stimulation. However, it is a great challenge to establish chiral OFETs to realize enantioselective sensing due to the same charging of the two enantiomers. Sun et al. developed an effective chiral OFET sensors by smartly assembling native b-CD onto copper-hexadecafluorophthalocyanin (F16CuPc) as the sensing unit (Fig. 4A) [58]. The constructed sensing platform is capable of probing subtle change of weak interactions between CDs and racemic chemicals, realizing fast and sensitive quantitative on-line analysis. Chiral resolution of ibuprofen (Ibu) in fetal bovine serum (FBS) was achieved, of which the concentration totally satisfied medical necessity [58]. Wu et al. applied an imidazolium 3,5-dimethylphenylcabamoylated-b-CD (Imþ-Ph-b-CD) as both the recognition unit and a quasi-gate to induce a secondary accumulation channel of electrons in the F16CuPc semiconducting layer [59]. As presented in Fig. 4B, without including analytes, the imidazolium moiety is included in the extended CD cavity resulting in the shielding of its positive charge. After addition of analytes, the hydrophobic moiety (ex. benzene ring) trends to push the imidazolium moiety out of the cavity owing to the stronger inclusion complexation. Consequently, charge-shielding effect on cationic imidazoliums is faded and the positive charge can act as a quasigate to induce more electrons in the n-type transistor to achieve

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signal amplification and chiral sensing. Wang et al. established a chiral OFET sensing platform with a CD-monolayer functionalized gold top-gate electrode for discrimination of diverse enantiomers including some neutral enantiomers [60]. Sensing mechanism was investigated by measuring the work function of the top gold electrode by photoelectron yield spectroscopy. Results demonstrate that SH-b-CD monolayer exhibits various surface potential after capturing different enantiomers leading to drain current changes.

3. Chiral-recognizing platforms based on optical signal In 1840s, Louis Pasteur separated two kinds of tartrate that crystallized in opposite crystal forms, and found different tartrate solutions were able to rotate the polarized light into opposite directions. The enantiomeric phenomenon then came to light in the field of chemistry. Chiroptical techniques becomes an important approach in chiral sensing, which can provide direct proofs for molecular chirality. For example, circular dichroism spectra are applicable for studying chiral recognizing mechanisms [61e63]. Except for the chiroptical techniques, there are also many other alternates without the need of polarized light for researchers to choose, such as photoluminescence (PL), electrochemiluminescence (ECL), Bragg diffraction, surface-enhanced Raman spectroscopy (SERS), UVevisible absorption spectra [64], etc. PL is a significant technique in chiral recognition, especially for enantiomers with fluorophores. Those emissive chiral molecules can be employed as fluorescent probes to indicate interactions with CD. Their inherent features including fluorescence intensity [65], fluorescence images [66], quenching [67] and relaxation kinetics [68], are all utilized to investigate discrimination processes in the way of detectable fluorescence signals. For example, Wang et al. used fluorescence images to indicate the molecular recognition, delivery and release ability of CDs-based materials upon doxorubicin hydrochloride (DOX) (Fig. 5A) [66]. Epirubicin hydrochloride (EPI) is the stereoisomer of DOX. Both of them are broad-spectrum antitumor drugs and have red emission. Under acidic condition, b-CD modified graphene oxide-magnetic nanocomposite has weaker complexing effect for DOX than EPI, as confocal laser scanning microscope (CLSM) images show (Fig. 5B). The result demonstrates that DOX can be targeting-delivered, and then controlled released into tumor cells by being loaded on the synthesized materials, which means that the synthesized

Fig. 4. (A) Schematic illustration of device configuration of the OFET-based sensor and the molecular structures of the F16CuPc and b-CDs (reprinted from Ref. [58] with permission from ACS). (B) Schematic illustration of chiral recognition mechanism for Phe enantiomers (reprinted from Ref. [59] with permission from ACS).

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Fig. 5. (A) Schematic illustration of the preparation of b-CD-functionalized magnetic graphene oxide and representation of loaded with DOX and EPI (reprinted from Ref. [66] with permission from RSC). (B) CLSM images of MCF-7 cells after incubation with MGC/DOX (a) and MGC/EPI (b) for incubation time of 0.5 h, 1 h, 4 h and 8 h (FV1000 CLSM, 20 objective lens) (reprinted from Ref. [66] with permission from RSC). (C) Optimized structure of the complexes formed between CD and Try and His enantiomers from sideview and planform. “Top” refers to the enantiomer entering the CD cavity from the secondary rim since CD clicked onto silica via the primary rim (reprinted from Ref. [70] with permission from RSC).

nanocomposite promises a bright future for stereoisomeric targeted-drugs. As for analytes without fluorophores, PL can be realized by employing an extra part, such as metal nanoparticles [69e71] and fluorescein [72] for fluorescence assays. Metal nanoparticles are widely used to implement two functions: fluorescing and immobilizing CDs. Zhou et al. employed nanoparticle probes containing CdTe quantum dots (QDs) that are encapsulated with silica followed by covalently linking silanized CDs to distinguish four types of chiral amino acids (AAs) [70]. The prepared probes exhibit improved stability and biocompatibility arising from encapsulation. Owing to the covalent bonding, the stability of nanoparticleassembled framework in water was enhanced and the loading capacity of CDs was optimized. The fluorescent sensor showed brilliant stereoselectivity towards AAs. The emission intensity discrepancy comes from different interaction affinity for the enantiomers. This distinguishing phenomenon may stem from the different penetration capacity of phenyl ring into the CD cavity. Density-functional theory (DFT) calculations provide in-depth information for the chiral recognition mechanism. AAs prefer to insert into CD from the secondary face since the primary face covalently bonded with silica has bigger steric hindrance. Two enantiomers exhibit different binding conformation with CDs (Fig. 5C). Except for changing fluorescence intensity, fluorescence recovery of the quenched dye is also a common strategy in chiral sensing. Specific interaction can interrupt the quenching process,

leading to that the combination in molecular level is immediately detected by emission turn-on. Aswathy et al. introduced AuNPs as the quenchers for fluorescein [72]. Before interacting with analytes, the emission from fluorophores restricted in CD cavity was quenched by fluorescence resonance energy transfer (FRET) between fluorophores and AuNPs. After addition of amino acids, CD turned to include specific isomers due to different binding force in competitive adsorption, resulting in the leave of fluorophore molecules from AuNPs and fluorescence recovering (Fig. 6A). ECL is a powerful sensing methodology having advantages of low background and high selectivity. It has attracted great interest in chiral discrimination. With high ECL efficiency, Ru (bpy)32þ is a crucial media in electrochemiluminescence system. The working mechanism is as follows: Ru (bpy)32þ immobilized on the electrode surface is firstly oxidized to Ru (bpy)33þ followed by reacting with radical ion which is produced by the analyte and then generating the excited state Ru (bpy)32þ*. Finally, energy is released from the excited state in the form of light emission. Based on this mechanism, Fu's group constructed a stereoselective ECL sensor [73], where AuNPs were used to immobilize Ru (bpy)32þ, and b-CDreduced graphene oxide (b-CD-rGO) was introduced to recognize proline (Pro) enantiomers. The results found that Pro, especially DPro, significantly enhanced ECL emission and different ECL intensities indicate the molecular steric interactions. They also designed a method based on both SH-b-CD and nanomaterials to distinguish AA and IAA [74]. As shown in Fig. 6B, CDs combined

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Fig. 6. (A) Schematic illustration of recognition mechanism for amino acids (reprinted from Ref. [72] with permission from Elsevier). (B) The fabrication process of the proposed ECL biosensor and the difference of ECL signals towards AA and IAA (reprinted from Ref. [74] with permission from Wiley). (C) ECL intensity-potential curves of Ru-b-CDeSHeGPCSCNN/GCE (1), Ru-b-CDeSHenafion/GCE (2), and Ru-GPeCSCNenafion/GCE (3) in 5 mM AA (a) and IAA (b), 0.1 M PBS (pH 8.5) was used (insets: ECL intensity-time curves, correspondingly) (reprinted from Ref. [74] with permission from Wiley). (D) B3LYP-D/6-31G(d) optimized geometry of the complexes formed between R- and S-propranolol and bCDs (reprinted from Ref. [77] with permission from RSC). (E) Schematic illustration of formation of g-CD pseudorotaxanes with the biphenyl-based axles (reprinted from Ref. [84] with permission from RSC). (F) Schematic illustration of geometry of association of (R,S)-()-EMT with a-CD (reprinted from Ref. [81] with permission from RSC).

with nanomaterials show synergistic effect in chiral recognition. The utilized nanocomposites are gold/platinum hybrid nanoparticles supported on multi-walled carbon nanotube/silica coaxial nanocables (GP-CSCN), which has high active surface area and prominent electronic transporting property. Therefore, GP-CSCN exhibits enhanced catalytic effect on the oxidation of AA/IAA to amplify the signal. Thiolated b-CD has been proved as the decisive element for discrimination of AA and IAA, because stereoselective interactions can only be implemented with the existence of CD (Fig. 6C). Molecular imprinting technique (MIT) is also proved to be effective in ECL sensor to discriminate cinchonine (CCN) from its enantiomer cinchonidine (CCD) [75]. SH-b-CD was implanted in magnetic molecularly imprinted polymer membrane, which has high selectivity to CCN with a low detection limit of 3.13 1011 mol/L. The structure of CCN may more suitably match the CD orientation and spatial configuration of the cavity than CCD. The effectiveness of the established method was further evaluated using human serum samples and obtained acceptable results. This work promises a satisfied future for stereoselective detection towards CCN in clinical diagnosis.

Bragg diffraction is an effective tool for rigorously describing crystalline structure. MIT can also be combined with Bragg diffraction for detection of L-Trp [76]. Yang et al. applied Bragg diffraction law to investigate swelling degree of CD molecularly imprinted photonic hydrogels (CD-MIPHs). CD-MIPHs was proved to possess higher stereoselectivity for L-Trp than imprinted polyacrylamide photonic hydrogels. CD nanocavities in the polymer matrix selectively capture chiral molecules and form stable complexes. Consequently, structural properties of hydrogels change, causing obvious Bragg diffraction shifts. Furthermore, SERS provides information on the fingerprint region of molecular vibration. With advantages of minimal or no water and CO2 interference, high information content and nondestructive analysis, Raman spectroscopy has been widely used for chemical analysis. Stiufiuc et al. exploited both SERS experiments and quantum chemistry to make full understanding of CD chiral recognition mechanisms for propranolol [77]. In SERS spectra of supramolecular complexes formed between R- or S-propranolol and CDs, different peak number and intensity were observed, illustrating the existence of distinct interaction modes. As given in

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results from theoretical calculations (Fig. 6D), R-propranolol has deeper insertion into b-CD cavity than S-propranolol via allowing naphthalene ring situate nearly vertically on the horizontal mean plane of CD.

4. Chiral-recognizing platforms based on magnetic signal Among diverse analytical techniques usually used, NMR has demonstrated superior capability in CDs-based enantiomers recognizing platforms, as the guest-host inclusion complexes can be observed at atomic level [78]. It not only grants a wonderful description of the supramolecular assembly, but also provides much critical information of host-guest complexes, for example, stoichiometry, association constants, conformations, symmetry, and dynamics [79]. As water-soluble chiral-solvating agents (CSAs), CDs tend to make enantiomers exhibit structure disparity in chemical environment, thus giving rise to different chemical shifts or peak shapes [80]. There are two possible mechanisms governing enantiomeric differentiation. One is that CDs and optical stereoisomers might form diastereomeric compounds that have diverse NMR spectrum [81]. The other is that CSAs may prefer to combine with one of the enantiomers rather than offer equal opportunity of complexing to both of them [82]. The chemical shift shown in NMR spectrum is an average value of bound and unbound substrates under equilibrium status [83]. The enantiomer that has larger association constant with CD owns a higher proportion of complexes, resulting in enantiomer differentiation. In practical applications, enantiomeric differentiation may involve those two principles at the same time. Generally, when the CD cavity size fits the analyte molecule, the best discrimination can be achieved. Compared to a- and b-CD, g-CD is not often used because of its relatively large cavity. However, Dai et al. implemented rotaxanation strategy to remarkably improve the capability in enantiomers resolution, where achiral linear molecules are introduced into g-CD cavity as axles to fabricate extremely unsymmetrical chiral binding sites, as illustrated in Fig. 6E [84]. The presented work provides a novel idea for designing chiral recognition platforms: the structure of chiral cavities including functional groups, shape and size, can be adjusted via implanting an appropriate spacer. It has been determined by NMR titration that a-CD can form a complex of 2:1 stoichiometry with fenchone molecules, a kind of bicyclic monoterpenoids [82]. There exist at least two binding sites in the complex system with complicated combination behaviors. The binding sites not just interact with fenchone, but also have affinity with other sites. Within host dimer capsule, the guest may have different equilibrium orientations and rotations of functional groups and thus three methyl signals of fenchone show large 1H and 13C chemical shift changes causing prominent differentiation. As for compounds containing fluorine atoms, 19F NMR provides a simple research process because 19F nuclei characterization is able to overcome the complexity of C and H spectra analysis. For example, emtricitabine (EMT) is a nucleoside reverse transcriptase inhibitor owning one fluorine atom and is applicable to the treatment of human immunodeficiency virus (HIV) infection. a-CD is found to afford high resolution for EMT enantiomers (Fig. 6F) [81]. With increasing a-CD concentration in EMT racemates, 19F NMR spectrum shows obvious separated doublet signals and the peaks are assigned to their relevant stereoisomers by spiking the sample solution with the (R,S)-()-EMT enantiomer. Except for chiral recognition, a-CD demonstrates good protecting capacity for some chiral drugs [85]. Sulforaphane is a kind of antitumoral drug with its isothiocyanate group as the antitumoral biological active site. CD hydrophobic cavity can incorporate the isothiocyanate group to protect it from reacting with water.

Iza et al. investigated the aggregation behavior of the synthesized chiral surfactant in detail by analyzing NMR signals of the inclusion complexes based on the interactions between b-CD and metallo-surfactants [86]. Pirnau et al. combined rotating frame NOE spectroscopy (ROESY) with 1D 1H NMR to provide evidence for interaction between b-CD and flurbiprofen (FP) [87]. Both chemical shifts and peak broadening reveals the complexation associationdissociation dynamic process. It is indicated by one-dimensional NMR that CD and FP can form complex with stoichiometry 1:1. ROESY provides qualitative information about the complex fine structure. For instance, the phenyl ring of FP inserts into CD through the cavity narrow face, and only a part of fluorophenyl ring is included in the hydrophobic cavum. X-ray crystallography is also applied for assisting NMR to further explain interactions between host and guest by revealing the structure information in details [88]. It reveals that the end of indole part of D-N-acetyltryptophan (D-NacTrp) is included in CD, while for L-enantiomer that part is completely outside the cavity. In an enantioselective process, the analyte apolar moiety generally enters CD cavum, and the newly modified functional groups on CD rims are supposed to specifically interact with analytes [89]. Derivatization of the hydroxyl groups is able to change the microenvironment of CD hydrophobic cavity, and alter CD geometry to achieve better inclusive fitness aiming at specific analytes. Numerous functional groups have been introduced onto CD rims such as aromatic rings [90], amino, methyl, etc [80]. Besides, there appear negatively or positively charged CD derivates, like trialkylammonium CDs [91], phosphated CDs [92] and sulfated CDs [93]. Benefitting from the derivatization, the range of CD applications in chiral discrimination has been significantly extended. For example, Puentes et al. investigated six phosphated CDs (P-CDs) as chiral NMR solvating agents for thirty-three cationic substrates with a wide range of structural characteristics [92]. The phosphate groups cause stronger steric hindrance, preventing mismatching molecules from binding sites. Moreover, charged groups provide better recognition towards cationic guests due to electrostatic interactions. For the investigated analytes, there is at least one kind of P-CDs to cause enantiomeric differentiation with both steric hindrance and electrostatic interactions participating in the enantioselective mechanism. In their work, paramagnetic lanthanide ions are also applied to enhance the enantiomeric differentiation. The magnetic field may perturb the chemical shifts and therefore enantiomeric differentiation can be enhanced. The results show that amplifying effect works in some cases. 5. Chiral-recognizing platforms based on macroscopic signal Although so many great achievements have been attained for chiral sensing by employing various techniques, more direct methods for enantiomeric discrimination are still being pursued with significant efforts. An ideal strategy is to translate enantioselective molecular recognition and discrimination events into visible signals at macroscopic level [94,95]. When CDs and enantiomers form diastereomeric compounds, they will have many different physical properties, among which crystallization behavior is the main one. Chatziefthimiou et al. reported that crystalline state of b-CD-L-NacTrp was obtained as a dimer structure [88], while b-CD-D-NacTrp does not crystallize from its aqueous solutions. Subtle discrepancy of the interaction between CDs and guest molecules is magnified during crystallization process, because the subtle difference can be immensely accumulated when a large number of complexes build bulk macroscopic crystalline together. Colorimetric analysis is also a method of visually recognizing enantiomers. Liu et al. synthesized b-CD-modified AgNPs to probe

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Fig. 7. (A) Schematic illustration of chiral recognition mechanism for Phe enantiomers (reprinted from Ref. [64] with permission from RSC). (B) Schematic illustration of chiral recognition mechanism for Trp enantiomers (reprinted from Ref. [96] with permission from Springer Nature).

chiral aromatic a-amino acids, including Phe, Trp, and Tyr [64]. Color changes caused by specific interactions with D-Phe, L-Trp or LTyr are easily observed by naked eyes. Additionally, quantitatively determination of the D-Phe percentage in a mixture of D- and L-Phe can be achieved according to appreciable yellow-to-red color changes. To figure out the enantioselective response mechanism, a series of control experiments were performed. The results show the b-CD is more inclined to interact with D-Phe than L-Phe. After binding with D-Phe, neighboring b-CD-modified AgNPs will aggregate together, because the inter-particle repulsive force (electrostatic and/or steric repulsion) is impaired by electrostatic attraction between eCOO- and eNH3þ of Phe (Fig. 7A), leading to the altered optical feature. Besides, Yang et al. employed CD-MIPHs to display the sensing behavior for a series of concentrations of L-Trp by an obvious color change [76]. Except for the approaches mentioned above, a facile way of chiral discrimination via macroscopic assembly was illustrated by Zheng et al. [96]. They prepared poly (acrylamide) hydrogels (pAAm-gels) bearing b-CD moieties (b-CD-gel) and pAAm-gels bearing D- or L-Trp (homochiral D- or L-Trp-gels). Homochiral D- or L-Trp-gels successfully inherit chirality from the corresponding amino acids. In NaCl aqueous solution, b-CD-gels can assemble with the L-Trp (3)-gels (3 denotes as the mol % of Trp in the reaction mixture for hydrogels synthesis) to cause an aggregate phenomenon whereas it does not interact with the D-Trp (3)-gels (Fig. 7B). Interaction sites exposed on the gel interfaces facilitate the specific aggregation behavior through enantioselective host-guest associations.

6. Challenge and perspective This review comprehensively summarizes the development of CDs-based chiral recognition platforms. Owing to the remarkable enantioselective capability of CDs, researchers have established numerous methodologies with good performance. Although the mechanisms in distinguishing enantiomers have been studied extensively, more accurate and exact molecular interaction model still requires to be revealed. It is necessary to figure out how stereoisomers are recognized, which is decisive for designing CDs and further improving related analytical strategies. Additionally, efficient, convenient, online and robust chiral discrimination approaches are still deficient in the applications of pharmaceutics and biomedicines.

Acknowledgments This work was financially funded by the National Natural Science Foundation of China (No. 21922409, 21976131, 21575100) and Tianjin Research Program of Application Foundation and Advanced Technology (18JCZDJC37500, 17JCYBJC20500).

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