Molecular Engineering of α-Substituted Acrylate Ester Template for

Article Cite This: Anal. Chem. 2018, 90, 881−887

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Molecular Engineering of α‑Substituted Acrylate Ester Template for Efficient Fluorescence Probe of Hydrogen Polysulfides Jingru Guo,† Sheng Yang,*,† Chongchong Guo,† Qinghai Zeng,§ Zhihe Qing,† Zhong Cao,† Jishan Li,‡ and Ronghua Yang*,†,‡ †

Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410114, P. R. China ‡ State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China § Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha 410013, P. R. China S Supporting Information *

ABSTRACT: In this article, hydrogen polysulfide (H2Sn)mediated Michael addition/cyclization cascade reactions toward acrylate ester analogues were exploited and utilized to construct novel and robust H2Sn-specific fluorescence probe for the first time. Through rational molecular engineering of the α-substituted acrylate ester template, the optimal candidate probe FP−CF3 containing trifluoromethyl-substituted acrylate ester group as recognition unit and 3-benzothiazol-7-hydroxycoumarin dye BHC as signal reporter can highly selectively detect H2Sn over other reactive sulfur species, especially biothiols including cysteine (Cys) and homocysteine (Hcy)/glutathione (GSH), with a rapid and significant turn-on fluorescence response (less than 60 s for response time and over 44-fold for signal-to-background ratio). The fast response and high selectivity of FP−CF3 for H2Sn could be attributed to a kinetically and spatially favored pentacyclic addition produced by the dual nucleophilic reaction of H2Sn with the CF3-substituted acrylate group. The big off−on fluorescence response is due to the pentacyclic intermediate results in the release of the highly fluorescent BHC. Moreover, it has been successfully applied in imaging of endogenous H2Sn fluctuation in living cells.

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probes proved to be highly selective, relatively high probe loading may be required during bioimaging applications due to the inevitable probe consumption by the competing reaction between template and intracellular biothiols. To address this issue, other H2Sn fluorescence probes have appeared based on some H2Sn-mediated specific reactions, including nucleophilic ring-opening reaction and benzodithiolone formation.19−23 Despite the fact that considerable efforts have been made as above, some limitations including low sensitivity, prolonged response times, and possible toxicity of relatively large recognition moiety are still present, hampering their further application to tackle biological issues. In response, novel sensing molecules that use easily accessible and biologically compatible recognition units with improved sensitivity and response times are needed. It was previously reported that acrylate ester containing α,βunsaturated carbonyl group is a powerful recognition template for biothiols Cys and Hcy via the conjugate addition/ cyclization sequence.24 On the basis of this biothiols-triggered

eactive sulfur species (RSS) are sulfur-containing molecules that exert crucial regulatory functions in biological systems.1−3Among them, hydrogen sulfide (H2S) has been deeply studied and recognized as an important endogenous gasotransmitter in the past decade.4 In contrast, as one member of RSS family and H2S derivates, hydrogen polysulfides (H2Sn, n > 1) have always attracted much less attention. Nevertheless, emerging evidence implies that H2Sn might act as the actual mediators in some physiological and/or pathological processes associated with H2S.5,6 It was also reported that H2Sn had higher potency than H2S during activating ion channels, tumor suppressors, and transcription factors.7 Although the significances of H2Sn molecules in redox biology have been acknowledged recently, their biological roles and detailed mechanisms of action are still poorly understood. Therefore, it is critical to develop effective tools for detection of H2Sn fluctuation in biological systems. Due to its advantages of high sensitivity, noninvasiveness, and spatiotemporal resolution capability, fluorescence molecular imaging is a promising approach for real time and in situ monitoring biologically important species of living organisms.8 Since the initial report by Xian et al.,9 several fluorescent H2Sn probes have been designed by exploiting 2-fluoro-5-nitrobenzoic ester template as recognition unit.10−18 Although these © 2017 American Chemical Society

Received: September 13, 2017 Accepted: December 6, 2017 Published: December 6, 2017 881

DOI: 10.1021/acs.analchem.7b03755 Anal. Chem. 2018, 90, 881−887

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cascade reaction, numerous Cys fluorescent probes have been developed over the past few years.25−32 Inspired by this approach and taking into consideration the bis-nucleophilic feature of H2Sn, we envisioned that acrylate ester analogues should also be able to trap H2Sn to give out pentacyclic leaving compound, resulting in the release of the masked fluorophore and then fluorescence recovery as shown in Scheme 1.

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EXPERIMENTAL SECTION

Synthesis of FP Series. The molecular structures and synthetic procedures of FP series are depicted in Figure 1. 3Benzothiazol-7-hydroxycoumarin BHC was first synthesized following the literature method.33Subsequently, these probe molecules can be readily prepared from BHC with corresponding acrylic acid through only one-step esterification reaction. Details for synthesizes and characterizations are included in the Supporting Information. Spectrophotometric Experiments. Stock solutions of each probe (5 mM) in THF were prepared in a glovebox. A PB buffer solution (10 mM, pH 7.4) with THF as the cosolvent (H2O/THF = 1:1, v/v) was used for performing all spectroscopic measurements. Test solutions were prepared by blending FP series and appropriate analyte stock into a tube and then diluting the solution to 500 μL with the PB buffer solution. After incubation at room temperature for 5 min, the absorption or fluorescence spectra measurements were then performed. The fluorescence spectra were recorded at emission wavelength range from 470 to 580 nm with excitation wavelength of 460 nm. Fluorescent Imaging in Living Cells. For imaging of exogenous H2Sn in living cells, the HeLa cells were stained with 2.0 μM FP−H and FP−CF3 for 20 min before being washed three times with PBS and then incubated with 100 μM Na2S4 solution for another 10 min. In order to monitor the intracellular endogenous H2Sn levels upon lipopolysaccharides (LPS) stimulation, RAW264.7 cells were stained with 5.0 μM FP−CF3 for 20 min under different conditions: (a) Cells only (control); (b−e) The cells were induced by LPS (2 μg/mL) for 0, 4, 8, and 12 h, respectively; (f) The cells were pretreated with DL-propargylglycine (200 μM) for 30 min and then treated as (e). After rinsing with PBS buffer, these cells were exposed to imaging experiment on the two-photon confocal microscope. Two-photon imaging patterns were obtained from the green

Scheme 1. Response Mechanism of α-Substituted Acrylate Ester Template toward H2Sn

Moreover, taking advantage of steric hindrance and electronic effects, conquest of biothiols interference and improvement of response performances would be achieved through rational molecular engineering of substituted acrylate ester analogues. Toward this end, we initiated a program to study the reaction between α-substituted acrylate analogues and H2Sn for constructing novel and efficient H2Sn-specific recognition template for the first time. We herein report the design, synthesis, and evaluation of a series of new H2Sn fluorescent probes, namely FP series, based on hydroxycoumarin fluorophore scaffold decorated with different acrylate derivates as recognition unit. One of them, FP−CF 3 bearing trifluoromethyl-substituted acrylate group, showed selective and fast response toward H2Sn with high sensitivity and was successfully used for intracellular H2Sn imaging.

Figure 1. (A) Molecular structures and (B) synthetic procedures of FP series. 882

DOI: 10.1021/acs.analchem.7b03755 Anal. Chem. 2018, 90, 881−887

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Analytical Chemistry

Table 1. Calculated Electrostatic Charges at the Enone βCarbon and Bond Dissociation Energies (BDES) at the Ester of FP Series

channel (480−560 nm) with two-photon excitation wavelength of 800 nm.

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RESULTS AND DISCUSSION Design Strategy and Mechanism Verification. As we know, coumarin derivates are frequently used fluorophores with

probe series

electrostatic charges, eV

bond dissociation energies, kJ·mol‑1

FP−H FP−CF3 FP−CH3 FP−Ph

−0.371 −0.253 −0.447 −0.397

280.65 278.23 249.38 270.23

FP−H is essentially nonfluorescent (ΦF = 0.006) in the aqueous buffer solution, whereas BHC is highly fluorescent (ΦF = 0.50) with maximum emission peak around 490 nm under the same conditions. Significant fluorescence differences between FP−H and BHC imply the possibility of realizing the “switch-on” fluorescent sensing approach. We then proceeded to investigate the response capability of FP−H toward H2Sn. Figure 2A illustrated that treatment of FP−H with Na2S4 solution as H2Sn donor elicited a dramatic fluorescence enhancement in pH 7.4 buffer solution at room temperature, accompanied by an obvious green color fluorescence appearance under a hand-held UV lamp. Notably, real-time reaction kinetics of FP−H with H2Sn in Figure 2B revealed that rapidly increased fluorescence intensity of FP−H reached a plateau in less than 1 min upon the addition of Na2S4 solution, indicating that acrylate ester template possesses the capture ability for H2Sn to quickly release the masked fluorophore. As a matter of fact, the response time of FP−H is shorter than that of most aforementioned H2Sn probes, which usually fulfill the response in the range of 10−30 min. It demonstrates that acrylate template would be beneficial for the real-time detection of H2Sn. In order to provide some insight into the mechanism of H2Sn-induced fluorescence enhancement of FP−H, we studied the reaction product of FP−H and Na2S4 by mass spectrometry analysis. MS data in Figure S1 revealed that new peaks appeared at m/z 119 and 295, indicating that pentacyclic compound 1,2-dithiolan-3-one was generated through Michael addition/cyclization cascade reaction to afford strongly fluorescent hydroxycoumarin derivate for a turn-on fluorescence response. Furthermore, superposition of thin-layer chromatography (TLC) spot and the normalized fluorescence emission spectra of the BHC and FP-H + Na2S4 also provide complementary proofs that the fluorescent product is the same as BHC (Figures S2, S3).

Figure 2. (A) Fluorescence emission spectra of 0.2 μM FP−H (a) in buffer solution (50% THF, pH 7.4) and its reaction with 1 mM Na2S4 solution (b), λex = 460 nm. Inset: the corresponding fluorescent color change (UV lamp, 365 nm). (B) Real-time fluorescence intensity records of 0.2 μM FP−H in buffer solution (50% THF, pH 7.4) upon additions of 1 mM Na2S4 solution. λex/λem = 460 nm/490 nm.

excellent characteristics including tunable emission and easy functionalization and small molecular size,34 from which various bioimaging probes have been derived over the past years.35−39 Moreover, it was recently reported that some coumarin derivates possess admirable two-photon properties,40−42 which should be beneficial for bioimaging due to the advantages of two-photon microscopy (TPM) such as reduced photobleaching of fluorophores, minimal autofluorescence background, improved penetration depth, and less photodamage to biological samples.43−45 Hence, 3-benzothiazol-7-hydroxycoumarin BHC was chosen as the fluorophore scaffold for constructing these designed probes by decorating with four different acrylate derivates, as depicted in Figure 1A. We anticipated that incorporation of these strong electron-withdrawing groups with BHC would significantly diminish the fluorescence via the PET and ICT mechanisms.46 In contrast, tandem addition of H2Sn into β-carbon and carbonyl position of acrylate template would generate the two-photon excitable and highly fluorescent BHC. In order to verify our design strategy, photophysical properties of BHC and probe FP−H were first explored after synthesis and structural characterization. Indeed, as expected,

Figure 3. (A) Fluorescence enhancement ratio (F/F0) of 0.2 μM FP series reaction with GSH, Hcy, Cys, and Na2S4, respectively. λex/λem = 460 nm/ 490 nm. (B) Kinetic plot of reaction of 0.2 μM FP series with 200 μM Na2S4. Inset: variations of the observed k′ versus kinds of FP series. 883

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Figure 4. (A) Fluorescence response of 0.2 μM FP−CF3 to Na2S4 (0−1000 μM) in PB buffer (pH = 7.4, containing 50% THF). λex = 460 nm. (B) Signal-to-background ratios (S/B) of FP−CF3 as a function of Na2S4 concentrations (0−1000 μM) in PB buffer (pH = 7.4, containing 50% THF). Inset: linear responses of S/B of FP−CF3 to changing Na2S4 concentrations (0−10 μM). (C) Fluorescence changes of FP−CF3 for Na2S4 in the presence of other common species in PB (pH = 7.4, containing 50% THF). The concentrations of Na2S4 and other species were 100 and 200 μM, respectively.

Molecular Engineering for Performance Evolution. As mentioned in the issue about biothiols-triggered cascade reaction toward unsubstituted acrylate ester, unsurprisingly, FP−H exhibited poor selectivity toward H2Sn over biothiols, especially Cys, at their physiologically relevant concentrations (Figure S4), consistent with the previously reported results by Feng et al.26 It implies that, although FP−H has sensing capacity for H2Sn, serious interference from intracellular biothiols would be an annoying shortcoming when bioimaging applications. To deal with such selectivity drawback, we focused on the substituted influence of α-carbon position on the acrylate ester template. Expectantly, increasing the steric crowding around α-carbon by substituted group would hinder the cascade reaction toward sterically demanding biothiols such as GSH, Cys, and Hcy. Nevertheless, for H2Sn with small molecular size, such steric hindrance effect would be out of action. In addition, the electronic perturbation from substituent may also influence response performances of probes by changing the electrophilicity of acrylate ester template. To verify the above hypothesis, three analogues, FP−CF3 bearing electron-withdrawing substituent of trifluoromethyl in the α-carbon position of acrylate ester template, FP−CH3 bearing electron-donating substituent of methyl, and FP−Ph with phenyl substituent, were synthesized. With these FP series in hand, their response performances toward H2Sn over biothiols were first evaluated. As can been seen from Figure 3A, all other nonfluorescent FP series can also be obviously lighted up after treatment with Na2S4 solution in pH 7.4 PB buffer, despite that they exhibited inferior fluorescence enhancement ratio as compared to unsubstituted FP−H.

More importantly, as we expected, the interference from biothols is significantly suppressed under its biologically relevant concentration for FP-CH3, FP−CF3, and FP−Ph, indicating that substituents play a crucial role in improving selectivity of acrylate ester template toward H2Sn via steric hindrance. Real-time reaction kinetics of other FP series with H2Sn were then examined by recording the variations in the emission intensity of wavelength at 490 nm. Figure S5 illustrates that all of them possessed fast response characteristics toward H2Sn similar to FP−H. It is noteworthy that electron effect of substituent exerts a certain degree of influence on the response rate of acrylate ester template. As depicted in Figure 3B, the time-dependent processes of their response toward H2Sn follow first-order kinetics with different observed rate constant k,47 the relevant observed rate constants of FP−CF3 bearing electronwithdrawing trifluoromethyl substituent (kFP−CF3 = 6.0 × 10−2 s−1) is about 1.5-fold larger than that of unsubstituted FP−H (kFP−H= 4.0 × 10−2 s−1), whereas FP−CH3 bearing electrondonating substituents exhibited inferior response rate toward H2Sn than FP−H. It manifests that electron-withdrawing substituent would be beneficial for acrylate ester template to capture H2Sn. To shed light on these substituent effects from a theoretical basis, computational calculations for these probes were carried out (Table 1, Figure S6). To our delight, the introduction of electron-withdrawing trifluoromethyl group increased the positive charge at the enone β-carbon of template (−0.253 eV of FP−CF3 versus −0.371 eV of FP−H), which would make it more electrophilic to handily react with nucleophilic 884

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Figure 5. (Upper row of images) Confocal fluorescence images of HeLa cells using 2.0 μM FP-CF3 (A) and FP-H (B) under different conditions. Left: loading with probe (A1, B1); middle: treatment with 500 μM Cys (A2), pretreated with 200 μM NEM (B2); right: in the presence of 100 μM Na2S4 solution (A3, B3). The images were collected at 480−560 nm upon excitation at 800 nm. Inset: the corresponding bright fields of cells. Scale bar: 30 μm. (Lower row of images) Quantification and comparison of mean pixel intensities obtained from the corresponding fluorescence images of FP−CF3 (C) and FP−H (D).

Figure 6. Effects of the LPS stimulation on the endogenous H2Sn levels in RAW264.7 cells. Confocal fluorescence images: (a) Cells only (control); (b−e) The cells were induced by LPS (2 μg/mL) for 0, 4, 8, and 12 h, respectively, and then incubated with 5 μM FP-CF3 for 20 min; (f) The cells were pretreated with DL-propargylglycine (200 μM) for 30 min and then treated as (e). The images were collected at 480− 560 nm upon excitation at 800 nm. Inset: the corresponding bright fields of cells. Scale bar: 30 μm. (g) Relative pixel intensities obtained from the corresponding fluorescence images.

contribute to high-quality fluorescence imaging for biological application. Response Performances of FP−CF3. Taking into account both the H2Sn reaction kinetics and fluorescence enhancement ability of FP series, FP−CF3 was chosen as the best candidate probe, and its capability for quantitative detection of H2Sn was successively evaluated. As is demonstrated in Figure 4A, the fluorescence emission spectra of FP−CF3 showed dramatic enhancement after the addition of increasing concentrations of Na2S4 solution (0 to 1000 μM). Observably, a signal to background ratio S/B = 44.48 (S/B = (F − Fbuffer)/(F0 − Fbuffer))48 was achieved in the presence of 1000 μM Na2S4 (Figure 4B), where F, Fbuffer, and F0 are fluorescence intensities at 490 nm of FP−CF3 with Na2S4, buffer and without Na2S4, respectively. Moreover, there was good linearity between the S/ B and the concentrations of Na2S4 in the range 0−10 μM with a detection limit (3σ/slope) of 50 nM (inset of Figure 4B), manifesting that FP−CF3 is potentially adaptive for quantitative determination of trace Na2S4 concentrations. It is of great importance for a bioimaging probe with highly specific response to the target molecule over other potentially competing species in the complicated biosystems. Therefore, except for Cys, evaluation on selectivity of FP−CF3 was extended to various biologically relevant species, including biorelated metal ions, reactive oxygen species, reducing agents, small molecule thiols, and other reactive sulfur species. As shown in Figure S7, besides Na2S4, other H2Sn donors including Na2S2, Na2S3, and the mixture of Na2S and NaClO also induce different degree of increase in fluorescence emission of FP−

sulfhydryl of H2Sn. In sharp contrast, electron-donating substituent exhibited opposite effect on the electrostatic charges of enone of template, indicative of inert reactivity of FP−CH3 relative to that of FP−H. For FP−Ph, the electrostatic charge of enone of template was slightly influenced by phenyl substituent due to the mutually offsetting result between electron-donating and conjugated effect of phenyl, which is in good agreement with the similar reaction kinetics between FP− Ph and FP−H. In addition, the bond dissociation energies (BDES) of the ester bond gradually magnify from 249.38 to 280.65 kJ mol−1 following the order trend of FP−CH3 < FP− Ph < FP−CF3 < FP−H, in accordance with the discrepancy of the fluorescence enhancement ratios of FP series. Obviously, the cleavage of the ester bond is more effortless as the BDES value is smaller, indicative of instability and higher background signal of probes. Therefore, the optimal fluorescence enhancement of FP−H upon treatment of H2Sn can be reasonably explained. In brief, calculated consequences are in accordance with reaction kinetics and fluorescence enhancement ratios of FP series. The above results definitely demonstrate that we can improve the response rate of the acrylate ester type probes and suppress the severe biothiols interference to a minimum level by rationally tuning steric and electronic effects of the recognition template. With the optimized probe, we would realize fast and selective response toward H2Sn, which might 885

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steric hindrance and electron effects, rational design and molecular engineering of α-substituted acrylate analogues and research on their responses toward H2Sn were carried out for the first time. After evolution of sensing performances, the optimal probe FP−CF3 bearing trifluoromethyl substitute was proved to possess excellent characters including rapid response, high sensitivity, positive selectivity over biothiols, and easy staining ability of living cells, thereby allowing robust visualization of intracellular H2Sn fluctuation. Above all, we propose a novel approach for designing molecular tools for exploring H2Sn chemical biology.

CF3. However, Figure 4C depicted that no obvious variations in S/B were observed in the presence of aforementioned interference biologically relevant species. These results demonstrate that the probe FP−CF3 shows excellent selectivity for H2Sn and possesses the ability to suitably detect H2Sn in complicated biological environments. Moreover, FP−CF3 is stable and could respond toward Na2S4 at a biologically relevant pH level (Figure S8), which promises further application of FP−CF3 to imaging of intracellular H2Sn. Living Cell Bioimaging. Given that FP−CF3 is highly selective, fast-responsive, and very sensitive under in vitro conditions, we set out to explore if these merits are effectual at a cellular level. Prior to the imaging experiments, low cytotoxic effect of this candidate probe had been confirmed by standard MTT assay (Figure S9). Subsequently, imaging experiments of living HeLa cells were carried out on two-photon confocal laser scanning microscopy. One can be found in Figure 5; the cells staining with FP−CF3 showed no detectable fluorescence signals yet began to emit strongly after incubation with Na2S4 solution. Moreover, gradually bright fluorescence can be visualized along with increasing concentrations of Na2S4 solution (Figure S10). In addition, time-dependent imaging of H2Sn inside live HeLa cells suggested that the fluorescence of cells dramatically increased with incubation time over only 3 min (Figure S11). These combined results indicate that FP−CF3 shows good cell permeability and is suitable for rapid visualization of intracellular H2Sn and monitoring of its concentration fluctuation. Different from FP−CF3, regardless of the presence of Na2S4, the contrast probe FP−H shows strong green fluorescence inside HeLa cells. In contrast, when pretreated with a known thiol trapping reagent N-ethyl-maleimide (NEM), no fluorescence was observed for another control cell staining with FP−H, indicating that significant interference from intracellular biothiols is present in the case of FP−H. To our delight, the free cells staining with FP−CF3 still keep silent even if treated with high concentration of Cys (Figure 5), manifesting that FP−CF3 is capable of selectively visualizing H2Sn over Cys inside living cells. It is widely acknowledged that H2Sn could be generated from cystathionine γ-lyase (CSE)-mediated cysteine metabolism,49and inflammatory mediators such as lipopolysaccharides (LPS) can induce the CSE overexpression.50 To demonstrate the intracellular level of H2Sn is associated with LPS, images of LPS-mediated H2Sn production in RAW264.7 cells using FP− CF3 were followingly performed. As depicted in Figure 6, with the increased stimulation time of LPS (2 μg/mL), cells stained with FP−CF3 displayed a gradually enhanced fluorescence signal. In sharp contrast, even though in the presence of LPS stimulation, fluorescence change remained slight when probeloaded RAW264.7 cells were preincubated with CSE inhibitor 51 DL-propargylglycine. These results indicate that LPS can upregulate the production of endogenous H2Sn by the CSE overexpression in RAW264.7 cells, and FP−CF3 is quite qualified for imaging endogenous H2Sn fluctuation in living cells.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.7b03755. Experimental details, synthesis, NMR and mass spectra, and additional spectroscopic data as noted in text (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Fax: +86-731-8882 2523. ORCID

Jingru Guo: 0000-0002-7784-0935 Sheng Yang: 0000-0003-0867-6438 Zhihe Qing: 0000-0002-6268-225X Jishan Li: 0000-0001-8144-361X Ronghua Yang: 0000-0001-7873-6892 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (21505006, 21735001, 21575018, 21605008, 31527803, 21545010), Hunan Provincial Natural Science Foundation of China (2017JJ3332), the Scientific Research Fund of Hunan Provincial Education Department (16C0033), the Open Fund of State Key Laboratory of Chemo/Biosensing and Chemometrics of Hunan University (2015011), and the Open Fund of Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation (Changsha University of Science & Technology) (2017CL03).

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CONCLUSION In summary, we found that acrylate ester, which is frequently used as the recognition template of reaction-based Cys fluorescent probe, can also take action toward H2Sn. To address the biothiols-interference issue for promising effective H2Sn detection with acrylate ester template, taking advantage of 886

DOI: 10.1021/acs.analchem.7b03755 Anal. Chem. 2018, 90, 881−887

Article

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DOI: 10.1021/acs.analchem.7b03755 Anal. Chem. 2018, 90, 881−887