Review
Fluorescent Probes Containing Selenium as a Guest or Host Di Wu,1 Liyan Chen,1 Nahyun Kwon,1 and Juyoung Yoon1,*
Selenium is an important trace element in living systems. Proteins incorporating selenium have a wide range of biological effects, ranging from anti-oxidant and antiinflammatory effects to the production of active thyroid hormones. In the past decades, selenium has drawn enormous attention because of its important role in biology, which can be ascribed partly if not solely to its redox and hard and soft donor properties. With the use of chemical mimicry, a large number of seleniumrelated fluorescent probes have been developed for monitoring physiological and pathological processes. This review, which summarizes recent progress made in this area, comprises two major sections. In the first section, fluorescent probes for selenium-containing species, such as selenocysteine (Sec), hydrogen selenide, thioredoxin reductases (TrxRs), and selenite, are described. This is followed by a discussion of fluorescent probes that contain selenium and detect reactive oxygen, nitrogen, and sulfur species, as well as cations and anions.
INTRODUCTION The element selenium was discovered by the Swedish chemist Jo¨ns Jacob Berzelius in 1817 and was named after the Greek goddess of the moon, Selene.1 As one of the chalcogen (ore-generating) elements, it exists in nature as six stable isotopes and a number of radionuclides with different characteristics. In the context of biology, selenium was long considered to be an absolute poison and even a carcinogen. However, this view was modified when Schwarz and Foltz2,3 discovered that selenium prevents liver necrosis in rats and serves as a micronutrient for bacteria, mammals, and birds. In recent decades, selenium biology has developed rapidly, and this element is now known in its multifarious forms as a required trace element in living systems. In humans, the nutritional functions of selenium are achieved through the action of 25 selenoproteins that have selenocysteine as their active center. These proteins have been linked to many health benefits in humans and other mammals, such as decreasing the incidence of cancer, protecting against cardiovascular diseases, treating particular muscle disorders, and delaying the onset of AIDS in HIV-positive patients.4 Thus, selenium has drawn greater attention in recent years, and many reviews have focused on this element.5–16 Fluorimetry is among the most simple, inexpensive, and rapid methods for detecting analytes (neutral molecules and ions). Probes based on this method have been investigated extensively and widely used in many fields because of their high levels of sensitivity and in particular their ability to be utilized for temporal and spatial sampling and in in vivo imaging applications. In the past decades, numerous fluorescent probes for monitoring species involved in physiological and pathological processes have been developed.17–21 On the occasion of the upcoming bicentennial celebration of the discovery of selenium, we prepared this review to summarize recent progress made in the
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The Bigger Picture Scientists have known for some time that selenium plays a significant role in a diverse range of physiological and pathological processes. Low levels of selenium are associated with an increased risk of mortality, poor immune function, and cognitive decline, whereas higher amounts have antiviral effects. Therefore, selenium continues to be heavily researched, and many new fluorescent probes have been devised to monitor physiological and pathological processes. However, several challenges still remain. Probes for biological selenium species remain limited because of the lack of highly selective reactions in which these species participate. More research, in particular theoretical calculations, is needed to provide insight into new reactions. As the bicentennial of the discovery of selenium by Swedish chemist Jo¨ns Jacob Berzelius in 1817 approaches, this review summarizes recent progress in the development of selenium probes. It is clear that more studies are required to uncover the mysteries of selenium.
Scheme 1. Structures of Probes 1–6 and the Corresponding Products of Reactions with Sec
development of selenium-related fluorescent probes. Although some closely related reviews have been published in recent years, none of them have covered fluorescent probes for significant biological Se species (selenocysteine [Sec], H2Se, thioredoxin reductases [TrxRs], and Se(IV)), which is a newly developed field.14–16 This review comprises two major sections. The first describes fluorescent probes for selenium-containing species, such as Sec, hydrogen selenide, TrxRs, and selenite. This is followed by a discussion of fluorescent probes that are related to the involvement of selenium in reactive oxygen (ROS), nitrogen (RNS), and sulfur (RSS) species, as well as in cations and anions. This review will be helpful for chemists and biologists working in this field. Furthermore, this review will encourage more readers to join in the effort to uncover the mysteries of selenium.
FLUORESCENT PROBES FOR IMPORTANT BIOLOGICAL SELENIUM SPECIES Fluorescent Probes for Selenocysteine Sec, a cysteine (Cys) analog with a selenol group in place of the thiol group, is genetically encoded as the 21st amino acid. Sec appears to be the predominant chemical form of selenium in biological systems; it is found to be specifically incorporated into selenoproteins (SePs) encoded by a UGA stop codon.6–9 Because of its low pKa value (5.8), the selenol group in Sec is almost fully ionized under physiological conditions. This feature leads to the high reactivity of Sec, which is responsible for the catalytic efficiencies of selenoproteins. Considering the important roles that Sec plays in selenite metabolism, reliable and rapid assays using biocompatible probes for this amino acid are in high demand. However, it is difficult to detect Sec because of the interference caused by high concentrations of biological thiols in cells, which have chemical properties that are similar to those of Sec. To date, very few fluorescence-sensing approaches for detecting Sec under physiological conditions have been reported. The first fluorescent probe for Sec was 30 -(2,4-dinitrobenzenesulfonyl)-20 ,70 -dimethylfluorescein (1; Scheme 1), described by Maeda et al. in
1Department
of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Korea *Correspondence:
[email protected] http://dx.doi.org/10.1016/j.chempr.2016.10.005
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2006.22 Indeed, this compound was first identified as a thiol probe.23 The quantification of glutathione (pKa(SH) = 8.5) with 1 was unsuccessful when carried out in media at pH values less than 7.0. Maeda et al. envisioned that careful selection of the pH of the medium would enable 1 to discriminate between selenols and thiols because the former substances have different pKa values and higher nucleophilicities. The results of the ensuing studies showed that the fluorescent responses of 1 toward Sec and thiols in sodium phosphate buffer in the pH range 5.8–7.4 were very different. The optimal discriminating ability of 1 toward Sec over Cys or DTT, reflected in an emission intensity ratio ISeH/ISH of over 200, occurs in phosphate buffer at pH 5.8. However, this assay is not compatible with biological environments, which generally have a pH value of 7.4. Thus, it is highly important to develop probes that selectively detect Sec over biological thiols under physiological conditions. Guided by the sensing mechanism utilized by thiol probes and the higher nucleophilicity of Sec (mainly present as selenolate at neutral pH), Zhang et al.24 designed and prepared a series of substances that have different electronic environments for the fluorescence quenching moiety and the linkage between the fluorophore and the quenching moiety. Among the substances explored, coumarin-based 2 (Scheme 1) was found to respond to Sec and other selenols in aqueous solution (pH 7.4) with more than a 100-fold increase in emission intensity. In contrast, biological thiols, amines, and alcohols did not promote fluorescence changes in 2. This strategy utilizes the better nucleophilicity of Sec (mainly present as selenolate) than that of biological thiols at neutral pH, as well as the good leaving character of fluorophores. The experimental detection limit of 2 for Sec is 0.5 mM, whereas the theoretical detection limit was calculated to be 62 nM. This probe was found to be sensitive enough to be used for quantifying the serum concentration of selenium in healthy adults (>500 nM), but it is not sufficient for accurate selenium determination in selenium-deficient patients with Keshan disease or Kashin-Beck disease (100 nM). Nevertheless, 2 is the first selenol probe that functions under physiological conditions and that has been used for quantifying the Sec content in TrxR and to imaging endogenous Sec in live HepG2 cells. It is worth noting that 2 is suitable for identifying selenol metabolites of various seleno-compounds in cells. This ability has led to clarification of the mechanism underlying the cytotoxicity of different seleno-compounds. In order to lower the detection limit of 2, Sun et al.25 designed the mechanistically closely related 3 (Scheme 1) by using a strategy that improves sensitivity by employing ring constraints to block rotation about the nitrogen and coumarin C7 carbon bond. As expected, 3 has a lower detection limit (18 nM) than 2 while retaining its selectivity for Sec. This probe was successfully applied to detecting endogenous selenols in single cells via flow cytometry as well as imaging selenol or Sec in zebrafish. It should be pointed out that 3 can be utilized to detect intracellular selenols with flow cytometry and to discriminate cancer cells from normal cells. In this effort, it was observed that cancer cells have higher intracellular levels of selenol-containing molecules than do normal cells. The fluorescent spectra of 2 and 3 have maxima that are located in the visible region, and as a result, they are only suitable for imaging studies in live cells and zebrafish. For live animal-imaging applications, the use of near-infrared (NIR) light (650– 900 nm) is advantageous because it causes lower photodamage to biological samples, it is capable of deep tissue penetration, and it has minimum interference from background autofluorescence of biomolecules in living systems and lower light scattering. Thus, NIR fluorescent sensors are highly desirable. Chen et al.26 used the
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Figure 1. Working Principle and Response Mechanism of the Polymer Micelle Probe for Sec Detection Reproduced from Nan et al. 32 with permission from The Royal Society of Chemistry.
chemistry based on the 2,4-dinitrobenzenesulfonamide reacting group along with an NIR dye to design the NIR 4 for Sec. The addition of Sec to 4 in PBS buffer (pH 7.4, containing 5% DMSO as a co-solvent) led to a 65-fold fluorescence enhancement at 712 nm along with a marked red shift from 596 to 690 nm in the absorption spectrum. Probe 4 is suitable for detecting Sec at physiological pH, and it responds within 10 min. The pseudo-first-order rate constant for the reaction producing emission enhancement was determined to be 1,644 min1; however, no detection-limit data were given. The probe can be utilized to image Sec in live cells and mice (Figure 1). Very recently, Areti et al.27 synthesized a series of dansyl derivatized triazole-linked glucopyranosyl conjugates and explored their use as fluorescent probes for Sec. Among these substances, 5 (Scheme 1) proved to be a highly sensitive and selective fluorescent probe for Sec. The probe reacts highly selectively with Sec in aqueous PBS buffer to release a fluorescent product in conjunction with a 210-fold fluorescence enhancement and a minimum detection limit of 150 nM. Probe 5 is water soluble because it contains the glucopyranosyl group, and as such, it serves as a model for the design of water-soluble fluorescent probes. Because the detection limit of 5 is higher than those of 2 and 3, it is not sufficient to detect Sec in patients with Keshan disease or Kashin-Beck disease. Probes 1–5 all use the nitrobenzenesulfonyl group as a fluorescence quenching moiety. The strategy used for designing these probes involves the use of electron density to govern the fluorescence-quenching moiety and reactivity of the linkage between the fluorophore and the quenching moiety. Through this approach, it is hoped that screening a number of candidates will uncover a probe with appropriate reactivity, high sensitivity, and selectivity to Sec. Kong et al.28 used another approach to develop a fluorescent probe for Sec. The design was motivated by observations made in their previous work, which showed that the Se–N bond involved in ebselen can be cleaved by a substance containing a sulfhydryl group with a high degree of selectivity. This finding led to the development of fluorescence methods for monitoring intracellular thiols and changes in their redox states (this work is discussed in the second part of this review).29–31 By using calculations, Kong et al. found
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Figure 2. Schematic Illustration of the Nanosensor for Detection of Selenol in Cancer Cells Induced by Na2SeO3 under Hypoxic Conditions Reprinted with permission from Hu el al.33 Copyright 2016 Elsevier Inc.
that the Se–N bond in 2,1,3-benzoselenadiazole is stronger than that in ebselen. In other words, 2,1,3-benzoselenadiazole has lower reactivity toward nucleophilic reagents than does ebselen. This result led them to design and synthesize the 2,1,3benzoselenadiazole-based 6 (Scheme 1). As expected, 6 reacts rapidly with Sec, but not with thiols. The product of the reaction between the probe and Sec has an emission maximum of 580 nm and a large Stokes shift of 120 nm. The limit of detection of 6 for Sec is 7.0 nM (SD = 3.5%, n = 11). Thus, 6 has the lowest detection limit among the probes mentioned above, except for 4 (data not given). In contrast to the Sec probes described above, which are all organic small molecules, a nanostructured fluorescent probe for Sec was reported by Nan et al.32 Although the probe is based on similar chemistry operating with 1, it can be used for selectively imaging Sec under biological conditions (pH 7.4). In the probe, the drug doxorubicin (DOX), serving as a fluorophore, is trapped in the polymer micelles (Figure 1). Sec cleaves the 2,4-dinitrobenzenesulfonate group, transforming the hydrophobic ends of the micelles into hydrophilic hydroxyl ends, leading to destruction of the micelles and liberating DOX. This nanomicelle probe was successfully applied to imaging endogenous Sec in cervical cancer tissues as well as in HeLa cells. Using this strategy, it should be possible to design similar micelle systems that can be used for controlled delivery of hydrophobic molecules for biomedical applications. Recently, Hu et al.33 reported the results of studies of an NIR fluorescent nanosensor for detecting selenols. The key design feature of this nanosensor is that the stability of the Au–Se bond is higher than that of the analogous Au–S bond, and the details of this strategy are illustrated in Figure 2. The nanosensor is composed of an assembly of peptide-chain-modified cyanine dyes linked to the surface of 13 nm gold nanoparticles (AuNPs) via stable Au–S bonds. Fluorescence from the cyanine dye is quenched by fluorescence resonance energy transfer, which occurs with the AuNPs. In the presence of selenol, the Au–S bond is cleaved efficiently by the formation of a stronger Au–Se bond with simultaneous release of the cyanine dye and recovery of its NIR emission. This nanosensor was successfully used for imaging changes in the selenol level in HepG2 cells during Na2SeO3-induced apoptosis. Moreover, the
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Scheme 2. Structure of Probe 7 and the Corresponding Products of Its Reaction with H2Se
results of mice experiments showed that tumor cell apoptosis induced by Na2SeO3 correlates with high levels of selenol under hypoxic conditions. This result is helpful for understanding the role played by selenol in cancer. In order to elucidate whether selenite-induced apoptosis of tumor cells in a hypoxic microenvironment can be ascribed to oxidative stress, Liu et al. developed a new selenol nanosensor f containing a 5-carboxyfluorescein fluorophore.34 They used this nanosensor together with a cyanine-dye-based hydrogen peroxide probe to investigate the scientific issues mentioned above. Adding selenol to a mixture of the two probes led to enhanced emission at 520 nm, whereas addition of H2O2 led to an increase in emission at 710 nm. The two probes were capable of simultaneously and differentially detecting selenol and H2O2 without interference. The results show that the selenol content in HepG2 cells increases slowly, and the H2O2 level experiences a rapid boost under normoxic conditions. However, under hypoxic conditions, the responses are the reverse. Given the above results, it is predicted that tumor cell apoptosis induced by selenite can be attributed to non-oxidative stress. However, much more work is needed to confirm this conclusion. Fluorescent Probes for Hydrogen Selenide Much like Sec can be regarded as the analog of cysteine (Cys), hydrogen selenide (H2Se) can be thought of as an analog of hydrogen sulfide (H2S). Although hydrogen selenide is an important selenium metabolism intermediate involved in many physiological and pathological processes, much less effort has been given to H2Se fluorescent probes. The fluorescent substance 7 was reported by Kong et al.35 to be a probe for H2Se. As shown in Scheme 2, this substance, which contains the same 2,1,3-benzoselenadiazole reaction center that is present in 6, emits in the NIR region, and it rapidly responds to H2Se with a high selectivity over H2S, Sec, and other biological thiols. Probe 7 was successfully used for imaging endogenous H2Se in live cells and in mice. Related studies showed that the mechanism for the anticancer effect of Se on hypoxic solid tumors is via non-oxidative stress. This conclusion is similar to that arising from another study by the same group (see above).34 In addition to 7, Wu and Zhao36 developed a cadmium sulfide (CdS) quantum dot (QD)-based probe for detecting hydrogen selenide ions (HSe ions). However, using this probe to detect HSe incurs interference from Cu2+ and S2, and therefore it has not been used in biological experiments. Fluorescent Probes for TrxRs Another set of important selenols containing biological molecules are the isoforms of TrxRs, which are found ubiquitously in all living cells and in different intracellular organelles. TrxR1 is predominantly located in the cytosol and nucleus, whereas TrxR2 is mainly localized within the mitochondria and TrxR3 is mainly expressed in the testis. TrxR is often overexpressed in many cancer cells, where it is believed to
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Scheme 3. Structures of Probes 8–10 and the Corresponding Products of Reactions with TrxRs
play an important role in tumor proliferation and drug resistance. Thus, there is a high demand for the development of convenient and direct methods for assaying the enzyme activities of TrxRs in live cells. However, only a few fluorescent probes for TrxR have been reported so far.37–39 The first fluorescent probe for TrxR, 8 (Scheme 3), was developed by Zhang et al.37 in 2014. A naphthalimide moiety serves as the fluorophore in this substance because of its outstanding light-emission characteristics, and a five-membered, cyclic disulfide scaffold, which can be selectively cleaved by TrxR in the presence of NADPH, serves as the reaction center. TrxR promotes cleavage of the S–S bond in 8. Cyclization then occurs to form a five-membered cyclic carbamate concomitant with release of the green fluorescing naphthalimide derivative. This probe was successfully applied to imaging TrxR activity in living cells and has the potential to be used for screening TrxR inhibitors in live cells, an important step for developing TrxR-targeted anticancer drugs. After this effort, Liu et al.38 designed and synthesized another mitochondrial targeting TrxR probe 9, which incorporates a triphenylphosphonium moiety into the parent probe 8 (Scheme 3). Probe 9, which is selective for TrxR2 (mainly localized within mitochondria), has been applied to assays of the enzyme in a model of Parkinson disease(PD) . The results of that investigation showed that TrxR2 is highly expressed in the model, thus providing a mechanistic link between TrxR2 dysfunction and the cause of PD. Probes 8 and 9 are both noncovalent labeling agents. Huang et al.39 demonstrated that the fluorophore released from these probes accumulates only around the protein-binding domain. The fact that nonspecific dissociation can be easily induced under highly dilute conditions could potentially limit the use of these probes in biological applications. As a result, these workers developed the covalent labeling probe 10, which contains a coumarin fluorophore (Scheme 3), for TrxR. Fluorescence from the coumarin moiety is quenched because of its conjugation with the substituted furan ring in 10 through an a,b-unsaturated ketone unit. This enables an intramolecular charge-transfer (ICT) interaction that causes excited-state
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Scheme 4. Structures of Probes 11–13
radiationless decay. In the presence of TrxR, a Michael-type reaction of the a,b-unsaturated ketone takes place, which results in disruption of the extended conjugation and elimination of the ICT process, a phenomenon that results in a turn-on fluorescent response. Although this covalent labeling probe is unique, much more attention needs to be given to developing TrxR probes for in vivo assays and imaging. Fluorescent Probes for Se(IV) Fluorescent probes for biologically significant organic Se species have been reviewed above. However, Se exists in inorganic forms as well, and these substances are more toxic than their organic counterparts. Selenium exists in four oxidation states, including elemental (Se0), selenide (Se2), selenite (SeO32, Se(IV)), and selenate (SeO42, Se(VI)). Se(IV) and Se(VI) each have a characteristic toxicity. The results of toxicological experiments demonstrate that Se(IV) is more toxic than Se(VI). Several fluorescent probes for SeO32 (Se(IV)) have been developed in the past by strategies involving coordination interactions, reactions with diamine groups, and interactions with nanostructures. Song et al.40 reported the 2-(2-formyl-4-methylphenoxy)-N-phenyl-acetamide probe 11 for Se(IV) detection (Scheme 4). This probe undergoes a dramatic fluorescence enhancement at 475 nm after coordination with Se(IV) in ethanol. Analysis of a Job plot indicates that 11 chelates with Se(IV) with 2:1 stoichiometry. The water solubility of 11 is not high, and this property could potentially limit its applications in aqueous environments. Feng et al.41 described the rhodamine 6G-based probe 12 for Se(IV) sensing. Probe 12 can be used in a water/ethanol mixture (0.5:9.5 v/v). Besides fluorescence enhancement, 12 also undergoes an obvious color change that enables the ready detection of Se(IV) with the naked eye. In addition, 12 participates in a 1:1 binding mode with Se(IV), and it has a detection limit of 2.8 nM. However, the water content of the system utilizing 12 as a probe cannot exceed 5%. Awual et al.42 developed the hydrazone-containing probe 13 to detect and remove Se(IV) from aqueous solutions. The limit of detection of 13 is 2.02 mg/L, and it can be regenerated and reused in many cycles without a significant deterioration of its performance. Se(IV) reacts with substances containing a 1,2-diamine group to form a piazselenol. Several fluorescent probes for Se(IV) have been designed on the basis of this reaction. For example, 2,3-diaminonaphthalene (DAN) reacts in acid medium with Se(IV) to form the fluorescent product, 4,5-benzopiazselenol, which emits around 550 nm. However, the use of this substance as an Se(IV) probe has some drawbacks, such as low water solubility, high toxicity, and insensitivity to trace amounts of Se(IV). To solve this problem, Martı´nez-Tome´ et al.43 designed a fluorescent Se(IV) probe that contains a sol-gel matrix in which a complex of DAN and 2-hydroxypropylb-cyclodextrin (HP-b-CD) is immobilized. This sol-gel matrix probe can be used for quantifying Se(IV) concentrations at submicromolar levels with a minimum detection limit of 13 nM and without the need for sample pre- or post-treatment. By utilizing a
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Figure 3. Nanoprobe Turn-On Fluorescence in the Presence of Se(IV) Reprinted with permission from Liang et al.44 Copyright 2013 American Chemical Society.
similar strategy, Liang et al.44 developed a Se(IV) nanoprobe that utilizes a silica nanoparticle matrix in which 3,30 -diaminobenzidine (DAB) is immobilized (Figure 3). When this nanoprobe selectively binds to Se(IV), it fluoresces at 530 nm upon being excited at 420 nm. The nanoprobe can operate in a solvent system composed of a 1:1 ratio of isopropanol to water. The DAD-based probe has a detection limit for Se(IV) of 0.19 ppm (2.41 mM) under optimal conditions. However, the presence of Cu(II) can reduce the response of this nanoprobe to Se(IV), but the addition of EDTA can minimize this interference. Chen et al.45 developed a novel Se(IV) probe composed of DAB linked to the surface of carboxyl-group-modified CdTe@SiO2. This nanoprobe can be used in a ratiometric mode for sensing Se(IV) with a detection limit as low as 0.53 ppb (6.68 nM), which is nearly three orders of magnitude lower than the probes described above. Other kinds of nanostructure-based probes for Se(IV) exist, such as those that utilize micelles and QDs. Zhu et al.46 reported the results of a study of micelle-capped Nile blue A (MCNBA) as an Se(IV) probe. The mechanism for the response of this probe involves oxidation of the micelle by selenite under neutral conditions (pH 7.0). The limit of detection of Se(IV) by this probe is 1.25 nM. Costas-Mora et al.47 described a CdSe QD-based Se(IV) probe that has a detection limit of 0.08 mg/L. This group used different techniques, including luminescence, UV-visible absorption spectroscopy, and total reflection X-ray fluorescence, to gain in-depth information about the mechanism of operation of this probe. The probes for Se(IV) described above are all based upon direct reactions or interactions with Se(IV). Two probes have been designed to detect Se(IV) by indirect methods. Wu and Zhao36 reported a cadmium sulfide QD probe for hydrogen selenide ions. Operation of this probe takes advantage of the fact that selenite reacts with glutathione (GSH) to produce hydrogen selenide ions, which are detected by changes in emission from the QDs. As a result, the probe in conjunction with GSH senses Se(IV) with a detection limit of 30 nM.48 Chen et al.49 used the same strategy to develop a room-temperature phosphorescent (RTP) Se(IV) probe that utilizes Mn-doped ZnS QDs. Quenching of RTP emission of Mn-ZnS QDs is a consequence of the production of HSe ions, generated by the reaction of selenite with GSH.
FLUORESCENT PROBES CONTAINING SELENIUM FOR OTHER SIGNIFICANT SPECIES Selenium-Containing Fluorescent Probes for ROS and RNS Fluorescent probes for important selenium species are described above. In this section, we summarize fluorescent probes containing selenium that detect ROS, RNS,
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Scheme 5. Structures of Probes 14–30 and the Corresponding Products Formed in Reactions with HClO/ClO
and RSS, as well as cations and anions. ROS and RNS play important roles in diverse physiological and pathological processes, including cancer and neurodegenerative disorders. Moreover, some ROS and RNS are present in the environment as pollutants. Thus, simple, inexpensive, sensitive, and rapid methods for monitoring ROS and RNS in vitro and vivo are of great importance. As a result of the advances made in selenium chemistry, selenium-containing fluorescent probes for ROS and RNS have been developed recently.17 For example, hypochlorous acid (HOCl), which exists in equilibrium with hypochlorite (OCl–) in aqueous solutions at physiological pH, is a powerful microbicidal agent in the innate immune system. However, excess amounts of this ROS can lead to many diseases. Thus, probes for detecting HOCl/ClO– have been investigated extensively, and several Se-based fluorescent probes have been reported. Li et al.50 developed the two coumarin-based probes 14 and 15 for detection of HOCl/ClO– (Scheme 5). Both probes display high selectivities and sensitivities,
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fast response times, and pH independence toward hypochlorite in vitro and vivo. The mechanism of operation of these probes involves oxidation of the phenylselenenyl group by HOCl/ClO–, leading to the formation of an intermediate selenoxide, which then undergoes spontaneous syn elimination to generate a coumarin dye. Compared with 14, probe 15 requires much larger amounts of NaOCl to complete the conversion. This observation is most likely a result of the fact that the syn elimination reaction occurring in 15 is restricted by the methyl group. Because of its lower detection limit (10 nM) and faster response time, 14 was utilized for fluorescence imaging of HOCl/ClO– in live cells. In addition, 14 can be used for monitoring HOCl/ ClO– in a myeloperoxidase (MPO)/H2O2/Cl– enzymatic system with great significance because MPO is abundantly expressed in primary azurophilic granules of leukocytes, including neutrophils and macrophages. Zhang et al.51 designed the reversible two-photon (TP) HOCl/ClO– probe 16, which contains a 9-fluorenone fluorophore covalently linked to two selenium-containing compounds (Scheme 5). Probe 16 displays weak fluorescence as a result of photoinduced electron transfer (PET) from the diphenyl selenide group to the excited state of the fluorenone moiety. Upon addition of HOCl/ClO– in HEPES buffer (pH 7.4, containing 10% DMSO as a co-solvent), Se atoms in the probe are oxidized to form Se=O groups, which do not participate in the PET quenching process. This causes the appearance of an emission maximum at around 520 nm and an excitation maximum around 415 nm for one photon and 800 nm for two photons. The detection limit of 16 for HOCl is estimated to be 0.35 mM. The probe was successfully used to track HOCl levels in zebrafish and mice because of the high resolution and deep tissue penetration of TP imaging. The reversible and TP features of the probe make it an ideal tool for further investigating the HOCl levels in live cells and in vivo. Lou et al.52 reported the results of an investigation of the 1,8-naphthalimide-based fluorescent probe 17 for HOCl/ClO–. As shown in Scheme 5, the weak fluorescence of 17 is proposed to be a consequence of PET quenching and an excited-state conformational-twist process, both involving the Se center. The PET process has been studied with the use of time-dependent density functional theory (DFT) calculations, and the excited-state conformational change has been verified by the results of experiments in which the viscosity and temperature were changed. In addition, the driving force of the twist was also investigated.53 After Se is oxidized to form Se=O by HOCl/ClO–, both the PET quenching and twisting processes are blocked. Thus, an enhancement in fluorescence intensity at 523 nm occurs. The detection limit of 17 for HOCl is estimated to be 0.586 mM. Finally, this probe has been used for visualizing HOCl and reducing repair in live cells and mice in situ. Qu et al.54 developed the lysosome-targeting HOCl/ClO– probe 18, which contains an aminoethyl-morpholine moiety. Confocal microscopy imaging of living cells indicated that the probe accumulates in lysosomes. However, the probe could be used only for imaging exogenous HOCl in living cells; imaging HOCl in stimulated RAW264.7 cells failed. The authors rationalized this observation by concluding that either endogenous HOCl is absent in lysosomes or the probe has an undesirable detection limit. Boron-dipyrromethene (BODIPY) has also been used as a common fluorophore-type signal transducer because of its high photostability, extinction coefficients, and fluorescence quantum yield. Several BODIPY-based probes for HOCl/ClO– have been reported (Scheme 5).55–59 The Han and Wu groups independently described two
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similar BODIPY-based probes, 19 and 20, respectively, in the same year.55–57 Both probes were applied to imaging HOCl in living cells. The detection limit of 20 was found to be 7.98 nM, and the limit of 19 was not determined. Manjare et al.58 developed two annulated BODIPY chalcogenides that were synthesized starting with respective bis(o-formylphenyl) dichalcogenide intermediates for detecting HOCl/ ClO–. Probe 21, whose structure was confirmed by X-ray diffraction analysis, is the first example of a substance containing selenium and tellurium directly attached to the pyrrole ring in BODIPY. However, the response rate and sensitivity of the Se-containing probe 21 are not as high as those of the Te analog. Probes 22 and 23, in which a phenyl selenide moiety is attached directly to the 2-position of the meso unsubstituted BODIPY system, were developed by the same group.59 Probe 23 fluoresces less efficiently than does 22 because of the effect of a heavy chlorine atom at the 6-position in the latter. The fluorescence intensities of both probes increase by ca. 18-fold (at 512 nm) and ca. 50-fold (at 526 nm), respectively, in the presence of HClO in a manner that corresponds to detection limits of 30.9 and 4.5 nM, respectively. Both 22 and 23 were successfully applied to imaging HOCl/ClO– in living cells. This group also reported studies of the diselenide-based dipyrazolopyridine probe 24 for HOCl/ClO–.60 This non-traditional and robust probe displays a high selectivity and sensitivity toward HOCl/ClO– over other ROS and RNS with a ca. 180-fold fluorescence intensity enhancement at 436 nm. The detection limit was calculated to be 0.36 mM. Although the probe was successfully applied to imaging HOCl in living cells, its short emission wavelength limits its practical application. Our group reported the development of the rhodamine-Se probe 25 for detecting HOCl/ClO–.61 This probe reacts with HOCl/ClO–, leading to an increase in its fluorescence intensity at 550 nm. However, the selectivity and sensitivity of 25 toward HOCl/ClO– are not as high as those of its S analog. Cheng et al.62 described the NIR HOCl/ClO– probe 26, composed of selenomorpholine incorporated in a heptamethine cyanine dye (Scheme 5). 26 is more sensitive for sensing HClO than its thiamorpholine analog. The probe shows very weak fluorescence in PBS buffer (pH 7.4). Upon addition of NaClO, the emission band at about 786 nm increases gradually and reaches a maximum (ca. 20-fold enhancement) after 2.0 equiv of NaClO is added. The detection limit of 26 was observed to be 0.31 mM. Probe 26 was used for detecting HClO in commercial fetal bovine serum and for visualizing HClO in live mice. Shen et al.63 used the same reaction center in conjunction with a 7-nitrobenz-2-oxa-1,3-diazole (NBD) fluorophore in a probe for detecting HClO (Scheme 5). Probe 27 exhibits highly selective, sensitive, and fast (<10 s) recognition of HOCl/ClO– in acetonitrile/PBS buffer solution (1:1 v/v, pH 7.4). The detection limit of 27 is 3.3 nM, which is lower than that of 26. Non-fluorescent, selenium-containing, pyrene-based probes 28–30 were developed by Chen et al.64 (Scheme 5). Probes 28 and 29 are rapidly oxidized by HOCl/ClO– in conjunction with the formation of respective pyrenyl-CH2Cl and pyrenyl-CH2OH blue emission bands. These probes also react with excess H2O2 to form pyrenyl-CHO, which emits blue-green fluorescence. However, reactions of the probes with H2O2 are slow, and therefore they do not compete with the HOCl/ClO– promoted reactions. Probe 30 reacts even more rapidly with HOCl/ ClO– over H2O2 in comparison with the corresponding reactions of 28 and 29, yet it yields the same product, vinyl pyrene, which emits at 392 nm. In addition to those detecting HOCl/ClO–, other Se-containing fluorescent probes for ROS and RNS have been developed. As mentioned above, Xu et al.29 showed
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Scheme 6. Structures of Probes 31–38 and the Corresponding Products from Reactions with ROS and RNS
that 31 serves as a reversible sensor for real-time imaging of redox changes taking place in vivo (Scheme 6). The probe contains a heptamethine cyanine fluorophore and ebselen as the reactive reaction site. Probe 31 is oxidized by H2O2, leading to formation of the ebselen moiety, a process that is accompanied by an enhancement of emission at 794 nm. In contrast, GSH promotes cleavage of the Se–N bond in the ebselen moiety in 31 along with fluorescence quenching. This probe, which has a high selectivity toward H2O2 over other ROS and RNS, was successfully applied to real-time imaging of changes occurring in intracellular redox states during apoptosis, as well as for monitoring changes in H2O2 concentrations at the wound margin in zebrafish larvae. Liao et al.65 reported the results of a study of the selenium-containing fluorescent ‘‘turn-on’’ probe 32 for monitoring hydrogen peroxide. This probe also contains an ebselen moiety, and it shows weak fluorescence in water because of the operation of a PET quenching process. Upon being oxidized by H2O2, the probe displays a strong fluorescence enhancement at 460 nm. In contrast, its analog, which does not contain an alkyl chain, exhibits no notable change in fluorescence intensity after being treated with H2O2. This phenomenon occurs because the product of the reaction of 32 contains a hydrophobic dodecyl chain that enables aggregation to form a micellar system, which restricts rotation and thus leads to aggregation-induced enhancement of fluorescence. Because of this feature, water is the only solvent in which the probe operates. Peroxynitrite (ONOO–) is a prominent biological RNS that is generated by radical combination of nitric oxide (NO) and superoxide (O2$–). This RNS is involved in a
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broad spectrum of physiological and pathological processes. Xu et al.66 reported the NIR organoselenium fluorescent ‘‘turn-off’’ probe 33 for ONOO– sensing (Scheme 6). The probe itself has an emission maximum at 800 nm when excited at 770 nm. Upon addition of ONOO–, 33 is converted to its oxidized state (Scheme 6), in which PET quenching occurs to weaken the fluorescence intensity. The resulting decrease in fluorescence intensity can be reversed by the addition of the reducing agent ascorbate. This redox cycle can be repeated at least eight times. Probe 33 was used for real-time imaging of cellular redox cycles in living RAW 264.7 cells. After this work, the same group described the polymeric micelle-based and cell-penetrating peptide-coated fluorescent nanoprobe 33, which incorporates a ONOO– indicator and a reference dye (isopropylrhodamine B [IRhB]).67 This probe enables ratiometric detection and imaging of ONOO–. ONOO– rapidly diffuses into the analyte-selective core of the nanomatrix in 33, where it reacts with the indicator and results in a decrease in the intensity of fluorescence while leaving the fluorescence from the IRhB fluorophore unchanged. In addition, this nanoprobe also has other attractive properties, including high water solubility, photostability, and biocompatibility, along with NIR excitation and emission capabilities. The detection limit of 33 was calculated to be 50 nM. This nanoprobe was successfully applied to imaging in ONOO in RAW264.7 cells, normal human liver cells (HL-7702), and human hepatoma cells (HepG2) because of its high selectivity and sensitivity. Yu et al.68 devised the reversible NIR fluorescent ‘‘turn-on’’ probe 34 for ONOO– sensing (Scheme 6). The modular probe also uses a cyanine dye as a high extinction coefficient fluorophore and 4-(phenylselenyl)-aniline as a modulator that enables a specific responses to ONOO– over other ROS and RNS. Probe 34 exits in a non-fluorescent state as a result of the operation of PET between the donor and acceptor groups. Addition of ONOO– causes an increase in emission from the probe at 775 nm (lex = 758 nm), a change that can be reversed by the addition of GSH. The emission enhancement at 775 nm is linearly dependent on the concentration of ONOO– in the range of 0–10 mM. Also, the probe was successfully applied to the detection of peroxynitrite in live cells. Another fluorescent probe, 35, containing a BODIPY moiety, was developed by the same group for peroxynitrite sensing (Scheme 6).69 The probe is highly sensitive and selective as a consequence of peroxynitrite-promoted oxidation at the organoselenium center under physiological conditions. The ensuing spirocyclization reaction at selenium gives rise to free 3-ethylamino-styryl-BODIPY in concert with an observable color change from purple to blue. In addition, the product displays blue fluorescence through an ICT mechanism. Also, the probe was successfully applied to detecting intracellular peroxynitrite levels in RAW264.7 cells. In another effort, this group developed the BODIPY-based, NIR-reversible organoselenium fluorescent probe 36 for assessing oxidation-reduction cycles mediated by HOBr and H2S.70 Initially, 36 exhibits a NIR emission maximum at 711 nm. After the addition of hypobromous acid (HOBr), the fluorescence intensity at 711 nm decreases, and a new emission peak at 635 nm arises. This change is a result of the fact that the electron-donating ability of the selenoxide is weaker than that of the selenide, which results in shortening of the donor-p-acceptor-conjugated system. The oxidation reaction can be reversed with H2S, which enables recovery of the original emission of the reduced selenium probe. The detection limits of 36 for HBrO and H2S were determined to be 50 nM and 0.1 mM, respectively. Furthermore, the fluorescent probe 36 has been utilized for real-time imaging of the HOBr/H2S redox cycles in living RAW264.7 cells.
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In continuing studies, Manjare et al.71 developed the diselenide-based BODIPY probe 37 for superoxide and thiols (Scheme 6). The probe, which was found to be selective and sensitive for superoxide over other ROS and RNS, operates via a fluorescence ‘‘turn-on’’ response at 514 nm (lex = 504 nm). The enhancement of emission is caused by monooxidation of both selenium centers in 37. Furthermore, the fluorescence response can be reversed by the addition of biothiols. The possible medicinal utility of the probe was demonstrated through its application to the detection of superoxide in live breast cancer cells (MCF-7/ADR cancer cells). Sun et al.72 reported studies on the rhodamine-based fluorescence probe 38 for detecting NO (Scheme 6). The probe itself displays only weak fluorescence because it possesses a less conjugated spirocyclic selenolactone structure. The probe was found to be selective and sensitive for NO over other ROS and RNS, as well as many other related species. The presence of NO in a solution of 38 caused an increase in the intensity of fluorescence at 585 nm when excited at 520 nm, as a result of opening of the spirocyclic selenolactone structure. The detection limit of 38 for NO was determined to be 38 nM, and its utility was demonstrated by detecting NO in HeLa cells. Selenium-Containing Fluorescent Probes for RSS Most of the probes described above are reversible given the redox property of selenium. Incorporating selenium into appropriate fluorophores is an ideal strategy for creating probes that have high sensitivity and selectivity for specific ROS and RNS. The same feature can be applied to the design of probes for RSS. RSS such as cysteine (Cys), homocysteine (Hcy), GSH, and hydrogen sulfide (H2S) play many important roles in biological systems in the same manner as do ROS and RNS. Several selenium-containing fluorescent probes for RSS have been developed in the past decades. For example, Zeng et al.73 reported a naphthalene-containing piazselenole (NDP) probe 39 for detecting GSH (Scheme 7). The probe displays a ratiometric fluorescence response with an enhancement in the ratios of emission intensities at 436 and 615 nm, accompanied by a change in color from jacinth to colorless. This probe exhibits a high selectivity toward GSH over related specials, including Cys. Zhu et al.74 developed the colorimetric and ratiometric fluorescent probe 40 for detection of 1,4-DTT, which is a powerful reducing agent and agent for protecting cells and tissues. As shown in Scheme 7, the probe is composed of 4-aminonaphthalimide as the fluorescing reporter, a self-immolative spacer, and a piazselenole group as the DTT responsive site. The probe responds to DTT selectively over other biothiols, including Cys and GSH. Upon addition of DTT, the piazselenole carbamate protecting group is cleaved, and 4-aminonaphthalimide is released. This chemical process is accompanied by an increase in emission intensity at 527 nm and a decrease at 461 nm. Good linearity was found to exist between the ratios of emission intensities at 461 and 615 nm and DTT concentration in the range of 5–60 mM. In addition, the utility of this probe for DTT was also demonstrated by its application to HeLa cells. The two probes described above are based on Se–N bond cleavage reactions of the 2,1,3- benzoselenadiazole group. Tang et al.30,31 reported an investigation of the fluorescent probes 41 and 42 for detecting thiols that operate through cleavage of an Se–N bond (Scheme 7). Probe 41, which is composed of a precursor to the rhodamine 6G fluorophore, was found to respond selectively to thiols over other related analytes.30 The strong nucleophilicity of the sulfhydryl group in thiols
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Scheme 7. Structures of Probes 39–47 and the Corresponding Product of Reactions with RSS
enables cleavage of the Se–N bond in 41, thereby restoring the strongly fluorescent dye rhodamine 6G. The probe shows good sensitivity (detection limit = 1.4 nM), and it has been applied to detecting intracellular thiols in HL-7702 and HepG2 cells. After this work, another rhodamine 110-based probe 42 for thiols was developed by the same group. This probe has a higher signal-to-noise ratio (up to 170-fold) than that of 41 (about 6-fold).31 The detection limit for GSH of 42 is 144 pM, and the probe has a fast response time of 5 min. Probe 42 has been applied to detecting intracellular thiols in a variety of cell types, including HL-7702 and HepG2 cells. Lou et al.75 developed the thiol probe 43, which is based on a fluorescein scaffold containing a diselenide bond (Scheme 7). In general, thiols cleave diselenide bonds five orders of magnitude faster than they do disulfide bonds. Upon addition of thiols, the diselenide bond in 43 is cleaved to yield selenenyl sulfide and selenol. This process is accompanied by the development of strong green fluorescence at 514 nm (lex = 488 nm). Upon treatment with hydrogen peroxide, the selenenyl sulfide and selenol products can be converted back to the original diselenide, thus providing the possibility of a reversible fluorescence readout for redox changes mediated by thiols. The limit of detection for GSH by 43 was established to be 0.225 mM, and
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the probe has been used for detecting thiols and the redox changes mediated by thiols and ROS in live cells. In 2015, Peng et al.76 reported a study of the diselenide-containing fluorescent probes 44 and 45 for H2S detection (Scheme 7). Probe 44 possesses a diselenide linked bis-coumarin fluorophore, and 45 has a similarly linked bis-fluorescein fluorophore. H2S reacts with the diselenide bond in these substances to form two intermediates. One is a thio-benzeneselenol derivative, which undergoes spontaneous cyclization to form 1,2-benzothiaselenol-3-one with release of the fluorophore. The other route forms an unstable benzeneselenol derivative, which rapidly oxidizes to reform the probe. Organo-thiols also react with the two diselenide-containing probes. However, these processes do not interfere with H2S detection because the resulting SSe-containing thio-benzeneselenol intermediate has a high reactivity with only H2S. Both probes show excellent sensitivity and selectivity toward H2S over related species, including thiols. Finally, 45 was used for imaging H2S in HeLa cells. Han et al.77 developed the diselenide-containing probe 46 for the sensitive and selective detection of cysteine hydropersulfide (Cys-SSH) (Scheme 7). The probe is composed of three moieties, including a bis(2-hydroxyethyl) diselenide as the reaction center, a heptamethine cyanine as the fluorophore, and D-galactose as the targeting unit. The detection mechanism for 46 involves a selenium-sulfur exchange reaction. The probe shows a ratiometric fluorescent response toward Cys-SSH. Upon addition of Cys-SSH, the maximum absorption of 46 changes from 790 to 614 nm with an associated color change from green to blue. In addition, a decrease in the fluorescence intensity at 797 nm takes place along with an increase in the intensity at 749 nm when excited at 730 nm and 614 nm, respectively. High linearity exists between the ratios of emission intensities at 749 and 797 nm and Cys-SSH concentration in the range of 0–12 mM, and the probe has a detection limit of 0.12 mM. The probe was applied for qualitative and quantitative detection of Cys-SSH in HepG2 and HL-7702 cells and in primary hepatocytes. In addition, the probe possesses an excellent liver-positioning capability. Kim et al.78 described the coumarin-containing probe 47 for detection of GSH (Scheme 7). The probe is composed of a coumarin as fluorophore and an aldehyde and a phenylselenide as two independent reactive sites. Probe 47 is non-fluorescent because of the existence of PET quenching. Upon addition of GSH, the fluorescence intensity at 518 nm is enhanced ca. 100-fold when excited at 471 nm. Under the same conditions, addition of other amino acids, including Cys and Hcy, does not change the non-emissive character of 47. Cys and Hcy do react with 47, but the products (Scheme 7) are non-emissive when excited at 471 nm. The probe has a rapid response rate, demonstrated by the observation that the maximum fluorescence intensity increase occurs within ca. 1 s, and an equilibrium is reached within ca. 100 ms. The probe has been successfully applied to imaging GSH in live cell systems. Recently, Lang et al.79 reported the development of a nanoparticle system composed of a selenium-containing anionophore for ultra-sensitive thiol-responsive anion transport. Initially, the activity of the nanoparticles is fully turned off because of an aggregation effect. Addition of thiols leads to reduction of the selenoxide group to form a selenide, a process that turns on the activity of the nanoparticles. The low detection limit of this probe makes this thiol-responsive transmembrane aniontransport system a promising candidate for biological applications.
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Scheme 8. Structures of Probes 48–63 for Cations
Selenium-Containing Fluorescent Probes for Cations and Anions Metal cations play significant roles in living organisms as protein cofactors. However, excessive amounts of metal ions or the presence of toxic metal ions has severe deleterious effects on living systems.15 In the past decades, several fluorescent probes for cations have been developed by a strategy that combines fluorophores and specific selenium-containing reaction or binding sites. An example of this type of probe is the one devised by Ma’s group and the selenolactone-based fluorescent probe 38, independently developed by our group (Scheme 8) for mercury (Hg2+) detection.80,81 We used probe 38, which contains a rhodamine B fluorophore, to monitor mercury and methylmercury species in vitro and in vivo. Ag+ ions also promote ‘‘turn-on’’ fluorescence of the probe, which has a detection limit for Hg2+ and Ag+ of 23 and 52 nM, respectively. The mechanism for the response might be associated with recognition by the selenium atom of bound Hg2+ and Ag+ and subsequent complex-promoted hydrolytic cleavage of the selenolactone bond, causing the release of rhodamine B and an enhancement in emission. In addition, as mentioned above, 38 also acts as a NO probe.72 Inspired by the antitoxic function of selenium toward heavy metal ions, Tang et al.82 designed the organoselenophosphate fluorescent probe 48 for Hg2+, which contains a fluorescein fluorophore (Scheme 8). The probe shows high sensitivity and selectivity toward Hg2+ over other relevant metal ions and bioanalytes. A plausible mechanism for the detection of mercury by this probe involves an irreversible deselenation reaction that leads to the formation of fluorescein. The detection limit of the probe is 1.0 nM for Hg2+, and 48 has also been used successfully for in vivo detection of mercury ions in RAW264.7 cells.
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Samb et al.83 synthesized and studied the phosphane selenide push-pull fluorescent probe 49 for Hg2+ (Scheme 8). The P=Se bond in the probe reacts selectively with Hg2+ over other relevant metal ions to form a P=O bond, leading to a ‘‘turnon’’ fluorescence response at 406 nm when exited at 330 nm with a detection limit of 0.9 nM. In contrast to the above-described selenium-containing fluorescent probes for Hg2+, which are all based on chemical reactions, coordination-interaction-based fluorescent probes for Hg2+ as well as other metal ions have been developed by Li et al.84 The colorimetric and fluorescent probe 50, which contains hemicyanine as fluorophore and NO2Se2 as a chelating unit to bind Hg2+ (Scheme 8), shows a selective decrease in fluorescence only with Hg2+ in both EtOH-H2O (1:1,v/v) and H2O over other relevant metal ions. Furthermore, the probe undergoes an obvious color change from red to colorless, which enables easy detection of Hg2+ with the naked eye. The detection limit of the probe is estimated to be 0.05 nM. Kumar and Singh85 developed the organoselenium-based NSe3 type tripodal probe 51 for Hg2+ detection (Scheme 8). This probe is special in that it does not require an external fluorophore as the reporting unit because the selenotripod itself, after formation of the Hg-Se bond, acts as the emitting species. The probe has a low Hg detection limit (0.1 nM) and an extremely short response time (15 s) at ambient temperature (25 C). Consideration of the strong coordination interaction between chalcogen atoms and Hg2+ led to the design of a series of Se-containing fluorescent probes for Hg2+, exemplified by 52.86 Probe 52 selectively detects Hg2+ with an association constant of 0.0152 in the presence of different interfering cations, including Zn2+, Cd2+, Cu2+, Co2+, Ni2+, Ca2+, Na+, K+, and Ag+. It is not possible to summarize work with all of these Se-containing fluorescent probes for Hg2+ in this review.86 Huang et al.87 reported work on the coumarin-Se2N-chelating conjugate fluorescent probe 53 for Ag+ (Scheme 8).87 The probe shows only weak fluorescence because of the operation of PET quenching, but it exhibits a highly selective fluorescence turnon response (4-fold enhancement) toward Ag+ over other relevant competing metal ions. The fluorescence enhancement is a result of inhibition of PET quenching. The detection limit of the probe was estimated to be 52 nM. After this effort, these workers developed probe 54, which is a bis-methoxy derivative of 53 (Scheme 8).88 Probe 54 also shows a high selectivity toward Ag+, and it has about the same detection limit as does the parent probe 53. Chou et al.89 used the same Se2N binding site along with a BODIPY fluorophore to construct the fluorescent probe 55 for Cu2+ (Scheme 8). The probe shows very weak fluorescence because of quenching caused by PET from the nitrogen atom of BODIPY, a proposal that was confirmed by DFT calculations. The probe shows significant fluorescence enhancement in the presence of Cu2+, whereas other relevant metal ions produce only negligible changes. The binding ratio of the probe and Cu2+ complexes was determined by a Job plot to be 1:1 with a detection limit of 0.87 mM. In addition, the probe has been successfully applied for detecting Cu2+ in RAW264.7 cells. Murale et al.90 developed probe 56, which is composed of a BODIPY moiety bearing a [Ophenol, Nt-amine, Se, Se] chelation pocket (Scheme 8). The probe is designed to detect ferric ions in the Fenton reaction. The probe is non-fluorescent in its unchelated state as a result of PET from the phenyl-4-amine-based donor group to the BODIPY fluorophore acceptor. After addition of Fe3+, the probe undergoes a
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15-fold ‘‘turn-on’’ fluorescence response. However, H2O2 can be used to turn off the fluorescence of the complex because H2O2 reduces Fe3+ to form Fe2+. On the other hand, Fe2+ together with H2O2 could lead to an enhancement of the fluorescence because H2O2 can oxidize Fe2+ to Fe3+. Thus, the probe can be used to discriminate between Fe2+ and Fe3+ via H2O2-promoted Fenton chemistry. Furthermore, the probe can be regarded as a 2:1 multiplexing molecular logic gate in which Fe3+, Fe2+, and H2O2 serve as chemical inputs. Mariappan et al.91,92 developed the anthraquinone-based organoselenium probes 57 and 58 for detecting metal ions (Scheme 8). Probe 57 exhibits fluorescence enhancement upon addition of Fe3+ and Cu2+ because of cleavage of the aryl-oxygen ether bond. The product, 1-hydroxy-8-(2-phenylselenoethoxy)anthracene-9,10dione, displays red-orange emission at 593 nm in CH3CN.91 After this work, the same group developed another series of fluorescent probes for Pb2+ detection on the basis of anthraquinone-bearing, heteroatom-substituted macrocycles (Scheme 8).92 Probe 58 exhibits an intense green emission (lem = 520 nm, lex = 390 nm) enhancement upon association with Pb2+ in acetonitrile. In the process, the probe forms a 1:1 complex with Pb2+ ions, which has been confirmed by spectroscopic titrations and X-ray crystallography. Panda et al.93 reported the results of a study of fluorenoazomethine-containing chalcogenides, including Se (59 and 60) as fluorescent probes for Cr3+, Fe2+, and Cu2+ (Scheme 8). The fluorescence signals of these probes are controlled by a conformational change undergone by the ligand framework upon binding with the metal ions. Initially, 59 and 60 show very weak fluorescence because of singlet excited-state decay by fast internal conversion and intersystem crossing. Upon addition of Cr3+ or Fe2+, both 59 and 60 show fluorescent enhancements as a result of conformational changes created by ion binding. The same group developed another ‘‘turn-on’’ probe, 61, for transition-metal ions that contains a reduced fluorenoazomethine group.94 The probe is weakly fluorescent because its flexibility allows the fluorophore to interact with the seleno-anisole motif and relax non-radiatively. Binding first-row transition-metal ions (Co2+, Fe2+, Fe3+, and Cu2+) creates a chargetransfer species that is effectively coupled to the ground state though a radiative relaxation pathway, making it highly fluorescent. Lei et al.95 described the conjugated polymer fluorescent probe 62 (Scheme 8), which utilizes benzoselenadiazole and triazole moieties as cooperative receptors of Ni2+. The probe shows ‘‘turn-off’’ fluorescence selectively toward Ni2+ over other relevant metal ions with a detection limit of 2.4 nM. Chen et al.96 reported the development of a peculiar ‘‘turn-on’’ fluorescent Zn2+ probe that contains a 2-p-tolyl-1H-imidazo[4,5-f][1,10] phenanthrolinium hydrogen selenite (HMPIP$HSeO3) moiety. The fluorescence intensity of the probe (lem = 500 nm, lex = 295 nm) is dramatically enhanced upon addition of Zn2+ in Tris-HCl buffer (pH 5.0). The titration curve and Job plot indicate that the stoichiometry associated with the response is 1:1. However, the mechanism and the role of the Se-containing counteranion have not yet been elucidated. Afzal et al.97 developed the ratiometric fluorescent probe 63 for Mg2+, which incorporates selenium in the azole moiety of fura fluorophore. The presence of Se in the probe results in a large shift in the emission wavelength and an increase in the Stokes shift. Furthermore, the introduction of Se affects the probe’s selectivity, dissociation constant, and cellular uptake properties, all of which are required for cellular uptake and detection of the ions. In addition, the probe was successfully applied to imaging intracellular magnesium in live HeLa cells.
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Scheme 9. Structures of Probes 64–66 for Anions
Se-based fluorescent probes for anions have been developed to a lesser extent than those for cations. Goswami et al.98 reported the fluorescent probe 64 for detection of carboxylate anions, which are present in many biological and physiological substances (Scheme 9). The probe is composed of a bulky pivaloyl group, which acts as a binding site, and the selenium-containing selenodiazole group, which serves as the signal-transducing unit. The probe shows good selectivity for carboxylate anions over carboxylic acids and other anions by displaying a remarkable fluorescenceenhanced and red shift. The possible binding modes of the probe are shown in Scheme 9. After this report, the same group uncovered another fluorescent probe 65 for aliphatic monocarboxylate anion detection.99 This probe has a structure that is similar to 64; the selenodiazole-fused pyrimidine ring acts as a signal transducer, and two acetylamine groups at the 2- and 4-positions act as the binding unit. The fluorescence maximum of the probe undergoes a significant bathochromic shift in the presence of a carboxylate ion. In addition, counter cations do not interfere with the selectivity of the receptor. Saravanan et al.100 designed the benzoselenadiazole-based colorimetric and ratiometric fluorescent probe 66 for fluoride (F) detection (Scheme 9). The probe shows a high selectivity and sensitivity toward F over other anions by its selective inhibition of an excited-state intramolecular proton-transfer process. Upon addition of F, 66 undergoes an obvious color change from intense red to dark blue, which can be observed with the naked eye. The intensity of fluorescence of the probe at 671 nm decreases with concomitant growth of a new band at 478 nm upon addition of fluoride. It is believed that fluoride-induced deprotonation inhibits PET quenching, which results in the disappearance of the normal emission from the probe and formation of fluorescence from a tautomer. In addition, the F detection limit of 66 was found to be in the submillimolar range.
CONCLUSIONS AND PERSPECTIVES Selenium is an important trace element in living systems, where it plays important roles not only in diverse physiological processes but also in various pathological events. In this context, fluorescent probes and bioimaging tools have been developed rapidly in the past decades because of the need to visualize biological species and monitor their concentration changes in live cells and tissues. On the occasion of the upcoming bicentennial of the discovery of selenium, we wrote this review to summarize recent progress that has been made in the development of selenium-related fluorescent probes. In this review, we have summarized a number of fluorescent probes based on small organic molecules and/or nanostructures for detecting important biological Se species such as Sec, H2Se, TrxRs, and the toxic inorganic
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Se(IV). Se-containing fluorescent probes used for detecting other significant species have also been discussed. Despite the progress made in designing and testing Se fluorescent probes, several problems and challenge still exist. Probes for biological Se species are still limited because the number of highly selective reactions that these species participate in is limited. As a result, an important issue that should be taken into consideration in designing new probes is the relationship that exists between the structure of the fluorescent probes and their selectivity and sensitivity toward guest species. For instance, incorporating the same reaction group, such as a selenodiazole, into systems containing different fluorophores could lead to probes that discriminate selenium species such as H2Se and Sec. Some Se-containing ROS and RNS fluorescent probes with the same reaction group and different fluorophores have been found to react selectively with hypochlorous acid, peroxynitrite, and hypobromous acid. Moreover, some probes for Sec have been selected through screening of a large number of candidates, a process that requires a large synthetic workload. We suspect that theoretical calculations could replace the screening approach. The following features, which are that same as found in other types of fluorescent probes, need to be considered in the design of fluorescent probes involving Se for biological systems. These include high selectivity and sensitivity, high photostability, low cytotoxicity, low self-oxidizability, good water solubility, good cell permeability, and low interference from substances in biological environments. Hopefully, this review will facilitate future efforts in the design of fluorescent probes involving SE and will encourage more chemists to work in this developing field.
AUTHOR CONTRIBUTIONS J.Y. proposed the topic of the review. D.W., L.C., and N.K. investigated the literature, and D.W. wrote the original manuscript. All authors read, revised, and approved the manuscript.
ACKNOWLEDGMENTS We are grateful to the editor for his kind invitation to submit this review. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (no. 2012R1A3A2048814).
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