Chinese Chemical Letters  2018, Vol. 29 Issue (10): 1456-1464   PDF    
Recent progress in Michael addition-based fluorescent probes for sulfur dioxide and its derivatives
Junchao Xua,b,1, Houqun Yuana,1, Lintao Zengb, Guangming Baoa    
a Institute of Veterinary Drug, Jiangxi Agricultural University/Jiangxi Provincial Key Laboratory for Animal Health, Nanchang 330045, China;
b School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China
Abstract: Sulfur dioxide (SO2) is a harmful environmental pollutant. Inhaled SO2 can be rapidly hydrated into its derivatives, bisulfite (HSO3-) and sulfite (SO32-). SO2 derivatives are well known as preservatives and antioxidants, which are used in food and beverages to prevent oxidation and bacterial growth. Although SO2 can be endogenously generated in mammals and exhibits unique bioactivities in regulating cardiovascular function, excessive SO2 and its derivatives have toxic effects on humans and animals for triggering adverse reactions and diseases. A large number of fluorescent probes for SO2 and its derivatives have been designed and reported due to their high sensitivity and selectivity, high temporal and spatial resolution, non-invasive and non-destructive detection as well as real-time visualization in situ. In this review, we have summarized the recent progress of Michael addition-based fluorescent probes for SO2 and its derivatives. These probes are categorized and concluded according to the different α, β-unsaturated compounds (i.e., Michael acceptors). The design strategies, sensing performances, detection mechanisms and applications of these probes are discussed in detailed. Finally, a general overview about the design of probes for SO2 and its derivatives is provided, which will facilitate the development of ideal probes for SO2 and its derivatives.
Keywords: Fluorescent probes     Michael addition     Sulfur dioxide     Bisulfite     Sulfite     Application    
1. Introduction

Sulfur dioxide (SO2) is a harmful environmental pollutant with a pungent, irritating and rotten smell, which predominantly produced from the combustion of fossil fuels and industrial processes [1, 2]. People who are chronic or acute exposure to SO2 may suffer from inflammation, irritation, respiratory diseases, lung diseases and even cancers. Inhaled SO2 can be rapidly hydrated into bisulfite (HSO3-) and sulfite (SO32-) in neutral solutions (1:3, M/M) [3]. SO32- is the physiological form of SO2 in vivo and also has toxic effects at certain concentrations in vascular and respiratory systems [4, 5]. Moreover, HSO3- and SO32- are also well known as preservatives and antioxidants, which are added in food (e.g., pickles, dried fruits and jams), beverages (e.g., concentrated tea, fruit juices, wine and beer) and pharmaceuticals to prevent oxidation and bacterial growth, and to control enzymic reactions during their production and storage [6-10]. However, ingestion excess amount of SO2 derivatives can cause asthma and allergic reactions [7, 11]. Considering SO2 and its derivatives adverse effects, Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO) have jointly suggested that an acceptable daily intake (ADI) of SO2 derivatives (expressed as SO2) for a healthy human should not exceed 0.7 mg/kg of body weight [12, 13], and United States Food and Drug Administration (FDA) allows 10 mg/kg or 10 mg/L of SO32- in food or beverages, respectively [14, 15]. These examples illustrate the importance of developing effective methods for the detection of SO2 and its derivatives in environment, biology and foodstuffs.

Fluorescence-based probe is a promising technique with overwhelming advantages, such as non-invasiveness and non-destructiveness, high sensitivity and selectivity, high temporal and spatial resolution as well as good bio-compatibility [16-27]. And it was reported that SO2 derivatives could be rapidly and quantitatively added to α, β-unsaturated compounds (i.e., Michael acceptors) in aqueous solution due to their strong nucleophilicity [28]. The strong electron withdrawing group (EWG) in Michael acceptor can reduce the electron density of carbon-carbon double bond, so electron-deficient olefin in Michael acceptor can be easily attacked by the nucleophilic reagents SO2 derivatives. Considering that the nucleophilic addition reaction between SO2 derivatives and Michael acceptors can change the electronic distribution and interrupt the π-conjugation, this reaction can be used for the development of SO2 derivatives fluorescent probes with excellent colorimetric and fluorometric responses (Fig. 1). In recent years, a large number of Michael reaction-based fluorescent probes for the detection of SO2 and its derivatives have been developed. This review aims to summarize the current progresses of Michael addition-based fluorescent probes for SO2 and its derivatives and inquire into the tendency of development in future. We wish that this review may be helpful for readers who are interested in this research field.

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Fig. 1. Sensing mechanism of Michael acceptor-based fluorescent probes for SO2 derivatives.

2. Design considerations for SO2 derivatives fluorescent probes

The ideal fluorescent probe for the detection of SO2 derivatives in environmental, biological or food samples should meet the following characteristics: (1) Good specificity. The probe should be high selective to SO2 derivatives over other ions and molecules, especially hydrosulfide (SH-), cyanide (CN-) and bio-thiols which possess nucleophilic reactivity that were similar to SO2 derivatives; (2) Excellent sensitivity. To guarantee a low detection limit, the probe should be high sensitive to SO2 derivatives under near physiological conditions [18]; (3) High reactivity. The probe should have high reactivity which means completing the sensing process within minutes, so that can real-time monitoring or visualization SO2 derivatives in vitro or in vivo; (4) Good bio-compatibility. The probe should have good bio-compatibility and membrane pene-tration to ensure good performance in bio-imaging [29]. Although rare probes satisfy all of these criteria, Michael addition-based probes have become the most popular and widely used agents for the detection of SO2 derivatives.

3. Unsaturated ketone-based fluorescent probes

Qian and Zhang et al. developed the first α, β-unsaturated ketone-based fluorescent probe (1) for the detection of HSO3- (Fig. 2) [30]. Probe 1 exhibited a colorimetric and ratiometric fluorescence response towards HSO3- in phosphate buffered saline/cetyl trimethyl ammonium bromide (PBS/CTAB) system with a detection limit of 0.2 μmol/L. The probe 1 was used to detect HSO3- in real samples with good recovery. Later, they reported two analogous fluorescent probes (2, 3) [31, 32]. The dual-analyte probe 2 which possessed an unsaturated ketone and an azido group could discriminate SO32- and SH-. Upon addition of SO32-, the nucleophilic addition between SO32- and unsaturated ketone was occurred, which led to the emission band dramatically shifted from 590 nm to 460 nm. However, the emission band of probe 2 shifted from 590 nm to 564 nm after reaction with SH- owing to the reduction of azido group. The probe 2 could be used to differentiate intracellular SO32- and SH- from different emission channels. The fluorescent turn-on probe 3 could discriminate SO32- and SH- based on the different reaction speed of the nucleophilic addition. SO32- led to an excellent colorimetric response within 10 min. Moreover, SH- caused a significant fluorescence enhancement and a dramatic color change after 2 h. The probe 3 was successfully applied for the biological imaging of SO32- and SH- in living cells.

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Fig. 2. Structures of unsaturated ketone-based fluorescent probes for SO2 derivatives.

Zhao et al. reported a two-photon (TP) fluorescent probe (4) for HSO3- detection [33]. Upon addition of HSO3-, it showed a dramatic color and fluorescence change. The detection limit of 4 was determined to be 53 nmol/L. The probe 4 could be made as test strip to detect HSO3-, which displayed different color and fluorescence in the presence of various amount of HSO3-. It was used to monitor HSO3- in tap water, sugar and dry white wine as well as in living cells.

4. Unsaturated nitrile-based fluorescent probes

Li and Yu et al. reported the first α, β-unsaturated nitrile-based fluorescent probe (5) for SO32- detection (Fig. 3) [34]. SO32- underwent the Michael addition to double bond, which interrupted the ICT process. 5 showed a colorimetric and ratiometric fluorescence response towards SO32-. The probe 5 was a fast response probe for SO32- with a detection limit of 58 μmol/L.

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Fig. 3. Structures of unsaturated nitrile-based fluorescent probes for SO2 derivatives.

Chen and You et al. developed a dual-analyte fluorescent probe (6) for the discrimination of HSO3- and hypochlorite (ClO-) [35]. The probe could report HSO3- and ClO- via the respective mechanism of nucleophilic addition and oxidation, resulting in a remarkable color and fluorescence change, and the probe-HSO3- adduct also could be oxidized by ClO-. The probe 6 was successfully used to quantify HSO3- and ClO- in living cells and visualize the dynamic of HSO3- and ClO- in zebrafish. Notably, 6 was able to successively respond to HSO3- and ClO-, which allowed a significant exploration on the dichotomous roles of SO2 derivatives under the ClO- induced oxidative stress in HeLa cells. Later, they reported an analogous TP ratiometric fluorescent probe (7) [36]. It also could discriminate mitochondrial HSO3- and ClO-. The probe 7 was successfully applied to detection of endogenous HSO3- and ClO- in living cells and image redox cycle between SO2 derivatives and ClO- in zebrafish (Fig. 4).

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Fig. 4. Two-photon microscopy (TPM) images of 7 for investigation of HSO3- and ClO- under intracellular oxidative stress (a) and antoxidative metabolism (b) in zebrafish. Reproduced with permission [36]. Copyright 2017, Royal Society of Chemistry.

Zeng et al. reported an aggregation-induced emission (AIE) based fluorescent turn-off probe (8) for the detection of SO32- [37]. With the assistance of the surfactant CTAB, the probe selfassembled into well-organized nanoparticles with yellow fluorescence. Upon addition of SO32-, the fluorescence was quenched due to the probe-SO32- adduct dissolved in water and interrupted the AIE process. Probe 8 could be made as test strip for SO32- detection, and it displayed different color and fluorescence in the presence of different concentrations of SO32-. The probe 8 was successfully used to detect SO32- in food and in living systems.

Zhou and Wu et al. reported a reversible ratiometric fluorescent probe (9) for the detection of HSO3- [38]. It displayed a colorimetric and ratiometric fluorescence dual-response towards HSO3- with a detection limit of 21 nmol/L. In addition, the probe-HSO3- adduct underwent an elimination reaction after the addition of oxidants (Iodine, I2), and the probe could be regenerated for circulatory monitoring of HSO3- through a redox-based tandem reaction. The probe 9 was successfully applied to monitoring the variation of HSO3- in HeLa cells.

Our group developed a colorimetric and ratiometric fluorescent SO32- probe (10) [39]. It showed a fast response (< 30 s) and high selectivity towards SO32- via nucleophilic addition reaction. The detection limit of 10 was determined to be 12 nmol/L. The probe 10 could be made as test strip easily and displayed different fluorescence in the presence of various amount of SO32-. Moreover, it was employed to determine the levels of SO32- in sugar with good recovery.

5. Unsaturated TCF-based fluorescent probes

2-Dicyanomethylene-3-cyano-4, 5, 5-trimethyl-2, 5-dihydrofuran (TCF) with three cyano groups exhibits strong electron-withdrawing property and better water solubility. It is extensively used in constructing far-red or near-infrared (NIR) fluorescent probes [40-43], because their emission can penetrate deeply through tissues with low auto-fluorescence background and reduce photo-damage to biological samples [44, 45].

Li and Yu et al. reported the first α, β-unsaturated TCF-based fluorescent probe (11) for SO2 derivatives detection (Fig. 5) [46]. The NIR fluorescent probe showed rapid, colorimetric and ratiometric detect of SO2 derivatives with a detection limit of 0.27 nmol/L. The probe 11 was used to detect SO2 derivatives in U-2OS cells with low cytotoxicity.

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Fig. 5. Structures of unsaturated TCF-based fluorescent probes for SO2 derivatives.

Zhao et al. developed a Förster resonance energy trtransfer (FRET) based fluorescent probe (12) for the detection of HSO3- [47]. The probe alone showed red fluorescence due to the FRET process from the coumarin fluorophore to the TCF moiety. Upon addition of HSO3-, the solution displayed coumarin emission with blue fluorescence, because the π-conjugation of TCF derivative was interrupted and the FRET effect was inhibited. The probe 12 was used to image of exogenous and endogenous HSO3- in living cells.

6. Unsaturated benzopyran derivative-based fluorescent probes

Yang's group developed two benzopyran derivative-based colorimetric and ratiometric fluorescent probes (13, 14) for SO32- detection (Fig. 6) [48, 49]. Upon treating with SO32-, the π-conjugation of the probe 13 was interrupted and the 'quinonephenol' transduction occurred simultaneously, which led to the excited-state intramolecular proton transfer (ESIPT). Moreover, the recognition reaction of 13 towards SO32- was reversible by addition of barium chloride (BaCl2). The probe 14 showed an obvious color and fluorescence change after addition of SO32-, because the nucleophilic addition of SO32- to the electrically positive benzopyrylium moiety altered the π-conjugated system. Both of them could be used for the fluorescence imaging of SO32- in living cells.

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Fig. 6. Structures of unsaturated benzopyran derivative-based fluorescent probes for SO2 derivatives.

Lin's group reported a TP and deep-red emission ratiometric fluorescent probe (15) for the detection of SO2 derivatives [50]. It showed an ultrafast response to SO2 derivatives (< 5 s) with a great emission shift (195 nm) and large emission signal ratios. The probe 15 was able to monitor and image SO2 derivatives in mitochondria of HeLa cells, mice brain as well as zebrafish under one-photon (OP) and TP modes (Fig. 7).

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Fig. 7. (a) 3D fluorescence images of 15 in the absence or presence of HSO3- in mice brain. (b) TPM images of 15 in the absence or presence of HSO3- in zebrafish. Reproduced with permission [50]. Copyright 2017, American Chemical Society.

7. Unsaturated aromatic ammonium-based fluorescent probes 7.1. Unsaturated indolium-based fluorescent probes

Yuan and Chang et al. reported an α, β-unsaturated indoliumbased fluorescent probe (16), which was the first mitochondria-targeted ratiometric probe for the specific detection of SO2 derivatives (Fig. 8) [51]. Upon addition of SO32-, it displayed a blue-shift in emission spectrum due to the π-conjugation was disturbed and the ICT process was inhibited. The probe was highly selective for SO32- and it was used to real-time monitor of intrinsically generated intracellular SO2 derivatives in mitochondria of HeLa cells (Fig. 9). Feng's group developed two NIR fluorescent probes (17, 18) with ICT property, which had similar structures to probe 16 [52, 53]. Both of them could rapid, colorimetric and ratiometric detect HSO3- and they were used for the detection of HSO3- in sugar samples and in HeLa cells.

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Fig. 8. Structures of unsaturated indolium-based fluorescent probes for SO2 derivatives.

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Fig. 9. Fluorescence images of 16 in the absence or presence of SO2 donor in HeLa cells. Reproduced with permission [51]. Copyright 2015, Elsevier B.V.

Feng et al. also developed a colorimetric and ratiometric fluorescent probe (19) for the detection of HSO3- (Fig. 10) [54]. As a large π-conjugation probe, 19 was a 'push-pull' electronic structure with the ICT property, and it showed red emission. Upon addition of HSO3-, the π-conjugation was interrupted, and led to the ESIPT process with the blue-green emission. The probe could be used for the rapid detection of HSO3- in food samples and in HeLa cells. Almost at the same time, Sun and Wang et al. developed a probe (20) that was very similar to probe 19, which also exhibited similar behavior for the detection of HSO3- [55]. The recognition process of 20 to HSO3- was reversible, and further addition of peroxides [e.g., hydrogen peroxide (H2O2) and tert-butyl hydroperoxide (TBHP)], the original probe could be restored. The reversible reduction-oxidation cycle could be repeated and still remained the reactivity and spectral properties. The probe 20 was applied to detection of gaseous SO2, monitoring HSO3- in water samples, and imaging the reversible redox cycle in living cells.

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Fig. 10. Structures of unsaturated indolium-based fluorescent probes for SO2 derivatives.

Zhang and Tan et al. reported a FRET-based TP fluorescent turnon probe (21) for SO2 derivatives detection (Fig. 11) [56]. The probe exhibited a very weak fluorescent because of the quenching effect from the acceptor (hemicyanine derivative). When the acceptor was interrupted by SO2 derivatives through addition reaction, resulting in the interruption of FRET effect with a significant fluorescent enhancement from the donor (acedan fluorophore). The probe 21 could be used for TP fluorescence imaging of biological SO2 derivatives in HepG2 cells and rat liver tissues. Almost at the same time, Yang et al. developed a ratiometric probe completely the same as probe 21, and it was able to visualize endogenous SO2 derivatives in mitochondria of HepG2 cells and rat liver tissues in TP mode (Fig. 12) [57].

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Fig. 11. Structures of unsaturated indolium-based fluorescent probes for SO2 derivatives.

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Fig. 12. TPM images of 21 under different conditions in fresh rat liver tissue slices. Reproduced with permission [57]. Copyright 2016, Royal Society of Chemistry.

Zhao's group also developed some FRET-based fluorescent probes (2225) for the colorimetric and ratiometric detection of SO2 derivatives [58-61]. The probes alone showed red fluorescence due to the FRET process from the donors [short emission dyes, e.g., dansyl, nitrobenzofurazan (NBD), hydroxyflavone and coumarin] to the acceptor fluorophores (hemicyanine derivatives). Upon addition of SO2 derivatives, the π-conjugation of hemicyanine derivative was interrupted by nucleophilic addition of SO2 derivatives, resulting in the interruption of FRETeffect with the donor emission. All of these probes were successfully used for imaging of exogenous and endogenous SO2 derivatives in living cells.

Wang's group reported two fluorescent probes (26, 27) for the detection of SO2 derivatives based on the FRET mechanism [62, 63]. The donors of the two probes were fluorescent carbon nanodots (CDs) and graphene oxide (GO), and the acceptors were hemicyanine derivatives. The fluorescence-enhanced probe 26 was demonstrated for the detection of SO2 derivatives in aqueous solution with a detection limit of 1.8 μmol/L. In addition, the probe could detect gaseous SO2 in aqueous solution as well as in air by assembling it on the test strip. The ratiometric fluorescent probe 27 was operated for gaseous SO2 both in solution and air with noticeable fluorescent color variation (from yellow to blue). The probe 27 was applied for sensing intracellular SO2 derivatives in MCF-7 cells with multicolor images.

7.2. Unsaturated benzoindolium-based fluorescent probes

Duan's group reported two α, β-unsaturated benzoindolium-based fluorescent probes (28, 29) for HSO3- detection (Fig. 13) [64, 65]. The detection mechanism of these two probes was that the π-conjugation interrupted by SO2 derivatives through the nucleo-philic addition reaction. The fluorescent turn-on probe 28 displayed a dramatic color change and fluorescent enhancement when exposure to HSO3-. The ratiometric fluorescent probe 29 showed an obvious color and fluorescence change after addition of HSO3-, and it was developed as paper test strip to identify HSO3- among other common ions. Both of them were able to detect the levels of HSO3- in sugar samples. Later, they reported an analogous fluorescent probe (30) for HSO3- detection [66]. The probe 30 with two electron acceptors, a benzoindolium fluorophore and a malononitrile group, was an electron acceptor-π-conjugation bridge-electron acceptor' (A-π-A') type compound. It could effectively avoid the severe emission quenching which was frequently encountered in electron donor-π-conjugation bridge-electron acceptor (D-π-A) type compounds. The probe displayed an obvious color and fluorescence change after exposuring to HSO3- with a very short response time (< 30 s). The probe 30 could detect the levels of HSO3- in sugar samples with good recovery and it was competent for imaging HSO3- in living cells.

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Fig. 13. Structures of unsaturated benzoindolium-based fluorescent probes for SO2 derivatives.

Our group developed a twisted intramolecular charge transfer (TICT) based fluorescent probe (31) for the detection of SO2 derivatives [67]. It showed a fast colorimetric and ratiometric fluorescence response to HSO3- with good selectivity and low detection limit (3.0 nmol/L). The probe 31 has been successfully used for visualization trace SO2 derivatives in A549 cells by the turn-on manner. In addition, the TICT effect made the probe as a molecular rotor, and it was able to measure solvent viscosity. Later, our group reported an ICT-based fluorescent probe (32) to improve the probe 31 [68]. It also displayed a colorimetric and ratiometric fluorescence dual-response to HSO3- with fast response (< 40 s), high selectivity as well as low detection limit (10 nmol/L). The probe 32 was a specific mitochondria-targeted fluorescent probe, and was used for monitoring the levels of intracellular SO2 derivatives in HeLa cells by the ratiometric manner (Fig. 14).

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Fig. 14. Fluorescence images of 32 under different conditions in HeLa cells. Reproduced with permission [68]. Copyright 2016, Elsevier B.V.

Li and Yu et al. developed two probes(33, 34) that were similar to probe 32, which also exhibited similar behavior for the detection of SO2 derivatives [29, 69]. The probe 33 was used to monitor the mitochondrial SO2 variation stimulated by certain kinds of drugs, which was potentially meaningful for studying diseases associated with SO2 derivatives. The probe 34 was designed to selectively discriminate SO32- and bio-thiols. SO32- reacted with conjugate bond as well as bio-thiols responded to aldehyde, and caused different absorption and fluorescence responses.

Das et al. eported a fluorescent probe (35) that was able to rapidly sense SO32- as well as sulfate (SO42-) through differential turn-on fluorescence responses [70]. The non-fluorescent solution of probe emitted a strong blue or greenish-yellow fluorescence upon interaction with SO32- or SO42-, respectively. The sensing of SO32- was explained by restriction in the ICT process due to the rupture of π-conjugation, while sensing of SO42- was attributed to that the higher hydration energy of SO42- facilitated the aggregation by lowering the solubility of probe and induced the AIE process with fluorescence emission. The probe 35 could demonstrate differential intracellular sensing of SO32- and SO42- in HeLa cells. Later, Yin and Li et al. developed a probe (36) with similar behavior as probe 35, which could detect SO2 derivatives and bisulfate (HSO4-) with different emission bands [71]. However, the mechanism of sensing HSO4- was based on ioninduced rotation-displaced H-aggregates. The probe 36 was also used to detect SO32- and HSO4- in HeLa cells through two emission channels.

Tian's group reported two A-π-A' type TP fluorescent probes(37, 38) for the detection of SO2 derivatives [72]. These two water-soluble probes displayed a colorimetric and ratiometric fluorescence dual-response to SO2 derivatives. They were used for the detection of SO2 derivatives in cancer cells or liver tissues under OP and TP modes.

7.3. Unsaturated benzothiazolium-based fluorescent probes

Guo et al. reported the first α, β-unsaturated benzothiazolium-based fluorescent probe (39) for the detection of SO2 derivatives (Fig. 15) [73]. The nucleophilic reaction of SO2 derivatives on the double bond caused interruption of the probe π-conjugation and blocked the ICT process through an addition-rearrangement mechanism. As a result, the initial red emission shifted dramatically to the coumarin blue emission as well as a distinct color change from violet to colorless. The probe 39 was successfully applied to detection of SO2 derivatives in HeLa cells.

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Fig. 15. Structures of unsaturated benzothiazolium-based fluorescent probes for SO2 derivatives.

Upadhyay et al. developed an ICT-based fluorescent probe (40) for the colorimetric and ratiometric detection of SO2 derivatives [74]. It exhibited high selectivity towards SO2 derivatives by disturbing the π-conjugation and the ICT process. The paper strip and thin layer chromatography (TLC) plate which coated with probe also displayed ratiometric fluorescent changes in the presence of HSO3-. Moreover, the probe was found to display AIE property with enhanced fluorescence emission and quantum yield upon increasing the water content of the medium. It was able to self-assemble into spherical particles, which underwent a noticeable morphological change in the size and shape upon addition of HSO3-. The probe 40 was used to detect HSO3- in the HeLa cells.

Chao et al. reported an ICT-based fluorescence turn-off probe(41) that was able to respond to HSO3-, CN- and extremely alkaline pH [75]. The probe showed supernal sensitivity and selectivity towards HSO3- in aqueous solution via 1, 4-addition reaction with red fluorescence turned off. In addition, it displayed excellent sensitivity and selectivity towards CN- in dimethyl sulfoxide (DMSO) also based on the 1, 4-addition mechanism with a remarkable fluorescence change (from orange to blue). Moreover, it exhibited a remarkable pH-dependent behavior with a pKa value of 9.75. The probe 41 was used to rapidly detect HSO3- in living cells, and it could image alkaline pH value fluctuations in Escherichia coli cells. Later, our group and Fan's group developed two mitochondria-targeted fluorescent probes (42, 43), respectively [76, 77]. They have similar structure to probe 41. The probe 42 showed a colorimetric (from yellow to colorless) and ratiometric fluorescence (from yellow to blue) dual-response to HSO3-. It could quantitatively determine the SO2 derivatives in several water samples with good recovery. The TP probe 43 showed real-time (35 s), excellent sensitivity (161 nmol/L) and high selectivity response towards SO2 derivatives. It was the first ratiometric fluorescent probe for monitoring exogenous SO2 derivatives changes in Daphnia magna through TPM (Fig. 16).

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Fig. 16. TPM images of 43 in the absence or presence of SO2 donor in Daphnia magna. Reproduced with permission [77]. Copyright 2018, Elsevier B.V.

Yin et al. developed a reversible NIR fluorescent probe (44) for the detection of HSO3- [78]. It showed a colorimetric (from violet to colorless) and ratiometric fluorescence (from red to green) dualresponse to HSO3- with rapid response (< 40 s) and low detection limit (95 nmol/L). Moreover, the recognition process of 44 to HSO3- was reversible. The probe-HSO3- adduct underwent an elimination reaction to restore the original probe after addition of H2O2. The probe 44 was successfully used to image the redox cyclebetween HSO3- and H2O2 in biological system by the ratiometric manner (Fig. 17).

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Fig. 17. Fluorescence images of 44 in MCF-7 cells under different conditions. Reproduced with permission [78]. Copyright 2017, American Chemical Society.

Zhao's group developed a FRET-based fluorescent probe (45) for the colorimetric and ratiometric fluorescence detection of HSO3- [79]. It was used to determine the levels of HSO3- in real samples and was prepared as paper test strip to monitor HSO3-. Moreover, the probe 45 was mitochondria-targetable, and was utilized to monitor both exogenous and endogenous HSO3- in living cells.

7.4. Unsaturated pyridinium-based fluorescent probes

Liu et al. developed the first α, β-unsaturated pyridinium-based fluorescent probe (46) for the colorimetric and ratiometric detection of SO32- (Fig. 18) [80]. The nucleophilic attack of SO32- towards the double bond interrupted the π-conjugation, and led to a dramatic color (from yellow to colorless) and fluorescence (from yellow to blue) change. The probe 46 can accurately determine SO32- with good sensitivity and selectivity.

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Fig. 18. Structures of unsaturated pyridinium-based fluorescent probes for SO2 derivatives.

Li and Yu et al. reported a pyridinium-based fluorescence turn-on probe (47) for selective detection of SO2 derivatives [81]. It exhibited a turn-on fluorescence response towards SO2 derivatives in water solution with a detection limit of 91.7 nmol/L. The probe 47 was successfully applied for imaging endogenously generated SO2 derivatives in HeLa cells with low cytotoxicity.

7.5. Unsaturated quinolinium-based fluorescent probes

Lin et al. developed an α, β-unsaturated quinolinium-based fluorescent probe (48) for SO32- detection (Fig. 19) [82]. It exhibited a wide dynamic concentration range for SO32- with high sensitivity and favorable selectivity. The probe 48 could be applied for ratiometric fluorescent imaging of SO32- in living cells with low cytotoxicity and high resolution.

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Fig. 19. Structures of unsaturated quinolinium-based fluorescent probe for SO2 derivatives.

8. Conclusions and perspectives

In this review, we have carried out a comprehensive account of research in the development of Michael addition-based fluorescent probes for SO2 and its derivatives. We addressed the design strategies, sensing performances, detection mechanisms and applications of these probes. Many probes were applied for food quality control, and they were successfully employed to determine the levels of SO2 derivatives in real samples (e.g., water, wine and sugar). Importantly, some of them could be used for determining endogenous SO2 derivatives, monitoring the enzymatic conversion of sulfur-containing amino acid cysteine (Cys) to SO2 as well as imaging the redox cycle between HSO3- and H2O2 in biological system, which were helpful for physiological or pathological research associated with SO2 derivatives. Compared to the unsaturated ketone- and nitrile-based fluorescent probes, unsaturated aromatic ammonium-based (especially indolium, benzoindolium, benzothiazolium) fluorescent probes are usually of better water-soluble and mitochondria-targeted, which could realize the concentration determination and imaging of endogenously generated SO2 derivatives. In addition, unsaturated aromatic ammonium-based fluorescent probes exhibit ratiometric sensing of SO2 derivatives, which are enable to furnish built-in self-calibration for correction of environmental effects and result in low auto-fluorescence interference, detection limit and high accuracy [68]. Moreover, the unsaturated TCF-based probes showed far-red or NIR fluorescence which can deeply penetrate through tissues. Although the exciting progresses have been made in this area during the past few years, significant challenges and problems still exist in the design and application of fluorescent probes for SO2 and its derivatives: (1) Exploiting highly sensitive and selective probe is essential because the concentration of SO2 derivatives in serum is at low levels (0–10 μmol/L) [83, 84] and the complex physiological environment contains many interferences (e.g., bio-thiols and SH-) which can interfere with the detection. (2) Most of reaction-based fluorescent probes for SO2 derivatives are typically irreversible, and hence they are incapable of mapping SO2 derivatives in a truly spatiotemporal manner [85, 86]. (3) The previously reported fluorescent probes for SO2 derivatives mainly focused on in vitro assay or cellular level bioimaging, but few probes was used for monitoring SO2 derivatives in vivo at subcellular or tissue level. Moreover, the function and distribution of SO2 derivatives in different organelles are remain unknown.

On the basis of the advantages and disadvantages of the present fluorescent probes, several future directions in this field should be followed to develop better probes and to exploit their further application. (1) Dual-analyte probes can discriminatively determine two analyte through different emission responses [87]. For dissecting the complicated roles (generation and metabolism) of SO2 derivatives in living systems, it is essential to develop dual-analyte probes for discrimination of SO2 derivatives and its relatives (e.g., bio-thiols, SH- and SO42-). (2) The reversibility of detection can obtain recyclable and reusable probes with high temporal and spatial resolution, and the reversible probes are of high availability owing to their circulatory detection ability, so it is important to develop reversible probes for circulatory detection of SO2 derivatives [38, 88]. (3) For bio-imaging applications, NIR and TP chemical probes should be exploited owing to that they can penetrate deeply into tissues and avoid damage to biological samples. Hence, organelle-targeted, water-soluble, TP excited TP excited fluorescent probes with NIR absorption and emission for specific, ratiometric, circulatory detection of SO2 derivatives could be an optimum goal. We envision that the cation-type FRET- or unsaturated benzoindolium-based reversible fluorescent probes with NIR absorption and dual-analyte properties will generate significant interest and be employed for optical imaging of SO2 derivatives in vivo in the next few years.

Acknowledgments

This work was financially supported by the National Key Research and Development Program of China (No. 2017YFD0501406), the National Natural Science Foundation of China (Nos. 31400301, 31560712).

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