Target-Triggered NIR Emission with a Large Stokes Shift for the Detection and Imaging of Cysteine

DOI:10.1002/asia.201402043

Target-Triggered NIR Emission with a Large Stokes Shift for the Detection

and Imaging of Cysteine in Living Cells

Chunchang Zhao,*Xiuai Li,and Feiyi Wang [a]

Abstract:Background autofluorescence from biological sys-tems generally reduces the sensitivity of a fluorescent probe for imaging biological targets.Addressing this challenge re-quires the development of fluorescent probes that produce emission in the near-infrared region.Herein,we report the design and synthesis of a fluorescent probe that generates an NIR emission with a large Stokes shift upon the selective response to Cys over Hcy and GSH.The probe is designed to consist of two Cys-sensing sites,an acrylate ester and an aldehyde installed ortho to each other.The reaction of the probe with Cys triggers an excited state intramolecular proton transfer process upon photo-excitation,thereby pro-ducing an NIR emission with a large Stokes shift.Accord-ingly,this probe hold great promise for the selective detec-tion of Cys in biological systems.We further demonstrate the capacity of this probe for Cys imaging in living cells.

Fluorometric detection of thiol-containing species has re-ceived intense attention due to their vital roles in biological systems.[1]Targets of particular interest are cysteine (Cys),homocysteine (Hcy),and glutathione (GSH).Deregulation of these biothiols is well known to be directly associated with cancer,Alzheimer s disease,neurotoxicity,retarded growth rate,hair depigmentation,liver damage,cardiovascu-lar diseases,and coronary heart disease.[2–4]The ability to monitor specific thiols in living cells has therefore great im-plications for the detection of disease states and screening of potential therapeutic agents.

So far,a number of fluorescent probes have been devel-oped for selective detection and applications in vitro and/or in vivo.[5–9]Most of the existing probes generally employ the strong nucleophilicity of the thiol group toward the func-tional moiety appended to the fluorophore as the sensing mechanism,which includes the Michael addition,[5]cycliza-tion reaction with an aldehyde,[6]cleavage of disulfide and sulfonamide,[7]and others.[8]However,most of them have

one major limitation with regard to the fluorescence re-sponse in biological systems,namely,interference from background autofluorescence by biomolecules.Addressing this challenge demands the development of fluorescent probes that produce emission at NIR range where autofluor-escence is significantly minimized.Although a few selective NIR sensors have been devised for the detection of biothiols in cellular processes,[9]the emission of these probes is gener-ally characterized by a small Stokes shift.A small Stokes shift can generally cause crosstalk between the excitation light and the resulting fluorescence signals,thus rendering measurements prone to error owing to the excitation light and scattered light,which interferes with the detection sensi-tivity to a great extent.[10]Thus,another important require-ment for decreasing the interference from autofluorescence by biomolecules,in addition to the NIR fluorescence,is the use of a dye that emits in the NIR region with a large Stokes shift.To the best of our knowledge,the construction of a NIR probe with a large Stokes shift for imaging the dis-tribution of biothiols in cellular processes has not been re-ported yet.

In this contribution,we report on the probe PCys-B that selectively responds to Cys over Hcy and GSH and emits in the NIR region with a large Stokes shift.Our design strategy was based on the considerations:1)Choosing a reaction as a suitable trigger for selective detection.Because of the sim-ilar structure and reactivity of thiol-containing molecules,it is still a challenge to construct probes that can discriminate one biothiol against other biothiols.Recently,a conjugated addition and cyclization reaction sequence has been ration-ally designed for the selective detection of Cys over Hcy and GSH.[8a,9c]Inspired by these elegant results,in this study,we therefore chose an acrylate group,generated by masking the phenolic hydroxy group in a BODIPY deriva-tive (Scheme 1)with an a ,b -unsaturated carbonyl moiety,as the sensing site to furnish such a reaction sequence and thus achieve the discrimination between thiols;2)Identifying a suitable fluorophore platform that meets the need of mini-mizing the background autofluorescence.It is well known that dyes exhibiting excited state intramolecular proton transfer (ESIPT)processes generally produce an emission with large Stokes shifts.[11]ESIPT can be observed in a varie-ty of molecules that contain both a hydrogen donor (usually the phenolic OH)and an acceptor (usually a heteroatom such as a nitrogen of a heterocycle)in close proximity to form intramolecular hydrogen bonds (H-bonds).Here,6-hy-[a]Prof.C.Zhao,X.Li,F.Wang

Key Laboratory for Advanced Materials and Institute of Fine Chemicals

East China University of Science&Technology Shanghai 200237(P .R.China)E-mail:

zhaocchang@https://www.360docs.net/doc/c919018541.html,

Supporting information for this article is available on the WWW under https://www.360docs.net/doc/c919018541.html,/10.1002/asia.201402043.

COMMUNICATION

droxyindole-based BODIPY was exploited as the fluores-cence scaffold to construct the sensing platform,as this dye has been reported to produce NIR emission around 650nm when it is in the phenolate form.[12]If a hydrogen acceptor is installed in close proximity to the phenolic hydroxy function of 6-hydroxyindole-based BODIPY,then ESIPT should occur upon excitation,and a rapid photoinduced proton transfer would result in the phenolate form with NIR emis-sion characteristics.Based on the above considerations,an aldehyde reaction group toward Cys was also positioned in the ortho position to the acrylate ester function.It can be envisioned that the reaction of Cys with the acrylate moiety in PCys-B could trigger the unmasking of the hydroxy group,while the cyclization reaction with the aldehyde could produce a thiazolidine.Since the amino group (H-bond acceptor)of thiazolidine is in close proximity to the hydroxy group,an H-bonding interaction through a six-membered ring therefore exists between them,and thus an ESIPT process could occur upon photo-excitation (Scheme 1).Indeed,the ESIPT phototautomer produces an NIR emission with a large Stokes shift,making PCys-B a promising probe for the selective detection of Cys with minimal background autofluorescence.We further demon-strate that PCys-B is cell-permeable and can be used for Cys imaging in living cells.

The synthesis of PCys-B commenced with the preparation of the intermediate BODIPY 1,as described in Scheme 1.

Condensation of 2-benzoyl-3-methyl-6-methoxyindole with 2,4-dimethyl-3-ethylpyrrole followed by treatment with BF 3·OEt 2afforded 1in 66%yield.Treatment of 1with DMF/POCl 3in CH 2Cl 2through a Vilsmeier–Haack reaction led to the formation of 2.Conversion of the methoxyben-zene moiety in 2to the corresponding phenol moiety in 3was then carried out following a standard deprotection pro-tocol using the reagent BF 3·SEt 2.Finally,the phenol moiety of 3was functionalized with acryloyl chloride to provide the probe PCys-B with a yield of 55%.The chemical structures of all new compounds were verified by 1H NMR and 13

C NMR spectroscopy as well as high-resolution mass spec-trometry (HRMS).

The spectroscopic characteristics of PCys-B were first evaluated in organic solvents of varying polarity.The optical features show profiles similar to those of typical BODIPY fluorophores (Figure S1,Supporting Information).The main S 0-S 1absorption transition band of PCys-B is centered be-tween 501and 521nm in pure solvents and shows a small solvent-dependent variation.Similar to the absorption spec-tra,the emission spectra also show a small solvent-depen-dent shift.Upon excitation at l max under ambient conditions,PCys-B was found to emit in the range of 537–551nm with high fluorescence quantum yields.Spectroscopic evaluation of PCys-B was then performed in a series of aqueous buffer solutions with varying acetonitrile content (Figure S1,Sup-porting Information).As can be observed from Figure S1

in

Scheme 1.Synthesis of PCys-B and proposed NIR sensing mechanism for Cys.

the Supporting Information,PCys-B exhibits a strong ab-sorption band in the visible region centered at 495nm in acetonitrile.When the concentration of CH 3CN in aqueous solutions was decreased from 100%to 10%,a red-shift from 495nm to 530nm in the absorption spectra was ob-served.The fluorescence spectrum of PCys-B exhibits an emission band around 541nm in CH 3CN.Changes in the concentration of acetonitrile results in little changes in the maximum emission wavelength (l em ).However,the emission intensity displays a dramatic enhancement with increasing acetonitrile content.

The sensory response of probe PCys-B is exemplified by its reaction with Cys under physiological conditions (aceto-nitrile/PBS buffer,1:1,v/v,0.01m ,pH 7.2,378C).In the ab-sence of Cys,PCys-B displays a strong absorption band at 495nm and exhibits an emission peak at 541nm.Upon ad-dition of Cys (1m m )to a solution of PCys-B ,a decrease in the absorption band at 495nm accompanied with an in-crease of a new band at 538nm was observed,thus resulting in a color change from orange to rose red (Figure S2,Sup-porting Information).This process displays a distinct iso-sbestic point at 508nm.It is noted that the ratio of the ab-sorbance at 538and 495nm increases over 7-fold,which en-ables Cys to be detected with the naked eye.

The fluorescence responses of PCys-B toward Cys were also investigated in buffer solutions.As shown in Figure 1b,

with the addition of Cys (1m m ),PCys-B displayed a drastic change in the spectral profile from a single-peak to a dual-peak profile.The emission intensity at 541nm was noted to decrease with a concomitant buildup of emission peaks at 574nm and 650nm upon excitation at 527nm.Consequent-ly,the fluorescence color changed from yellow to red under illumination with a UV lamp (Figure S2,Supporting Infor-mation).The ratio of emission intensities at 650and 541nm (I 650/I 541)increased 17-fold,thus enabling more accurate measurements of Cys by using the ratiometric response of PCys-B .By monitoring the changes in the fluorescence in-tensity ratio at 650and 541nm (I 650/I 541),the observed rate constant was then determined to be 0.12min à1

under

pseudo-first-order conditions (Figure S3,Supporting Infor-mation).It is worth mentioning that PCys-B produced an NIR emission at 650nm upon excitation at 527nm in the presence of Cys,thereby exhibiting a large gap of 123nm between the excitation wavelength and the emission wave-length which can effectively diminish any measurement error caused by the excitation light and scattered light.Exci-tation at 538nm,the maximum absorption wavelength of the product generated by the reaction of PCys-B with Cys,could also elicit an NIR emission at 650nm (Figure S4,Sup-porting Information),thus exhibiting a large Stokes shift of 112nm.These data indicated that PCys-B could serve as a promising probe for the detection of Cys with minimal background autofluorescence.The above observed change in the emission profile was ascribed to the reaction of Cys with the two appended functional groups acrylate and alde-hyde in PCys-B .Cys triggered the unmasking of the acrylate ester,thus leading to the release of the phenolic hydroxy-based BODIPY which produced the emission at 574nm.The reaction between Cys and aldehyde introduced the for-mation of a thiazolidine.Since the amino group in the thia-zolidine is in proximity to the phenolic hydroxy function,an intramolecular H-bond formed through a six-membered ring.Then ESIPT occurred upon photo-excitation,resulting in the emission at 650nm with a large Stokes shift.The con-version of PCys-B to the corresponding product was also confirmed by HRMS characterization (Figure S5,Support-ing Information).The effect of pH on the response of PCys-B to Cys was also investigated (Figure S6,Supporting Informa-tion).A distinct enhancement of the I 650/I 541ratio could be ob-served when the pH was in-creased from 6to 8.This phe-nomenon could be attributed to increasing deprotonation under basic conditions,which results in the phenolate-based emission in the NIR region.Apparent-ly,PCys-B can serve as a prom-ising ratiometric probe for Cys within the physiological pH window.

We further examined the efficiency of PCys-B in the mea-surement of Cys at various concentrations.Figure 2shows a plot of the fluorescence intensity ratio of PCys-B as a func-tion of Cys concentration.Evidently,the ratio increased lin-early with increasing concentration of Cys up to 400m m (es-sentially covering the physiological levels of Cys between 240and 360m m ),thus demonstrating that PCys-B could

detect Cys both qualitatively and quantitatively.The detec-tion limit was determined to be 2.33 10à7m ,which is com-parable to that of previously reported probes.PCys-B showed a good selectivity for Cys over other reac-tive sulfur species and other biologically relevant amino

acids.The specificity of the probe was examined by measur-ing the response after incubation with various related

spe-Figure 1.(a)Absorption and (b)emission spectra of PCys-B (10m m )after incubation with Cys (100equiv)in

acetonitrile/PBS buffer (1:1,v/v,0.01m ,pH 7.2)at 378C for 0,1,2,3,4,5,6,8,10,15,20,25,30,and 40min.

l ex =527nm.

cies in buffer solution.In the case of Hcy and GSH,two structurally related amino acids,no dual-peak emission spec-tra profile could be observed,although these amino acids caused a small red-shift in the emission of PCys-B .By con-trast,Cys introduced a remarkable change in the profile of the spectra from a single-peak to a dual-peak profile (Fig-ure 3a).Furthermore,the dramatic change in the fluores-cence intensity ratio of I 650/I 541over time could only be ob-served in the presence of Cys (Figure 3b).Other related amino acids triggered no obvious changes in the emission spectra,as shown in Figure S7in the Supporting Informa-tion.Therefore,PCys-B is a highly selective probe and can monitor Cys with minimum interference from other relevant analytes.

We further examined the potential usefulness of PCys-B for live cell imaging of Cys.As shown in Figure 4,MKN-45cells incubated with PCys-B for 20min at 378C showed a strong fluorescence in the NIR region (650–700nm)as a result of the ESIPT process,whereas a faint fluorescence signal from the unreacted original probe could also be ob-

served in the green channel at 500–550nm.The ratio of the emission intensity in the green channel to that in the red channel was around 0.3.By contrast,MKN-45cells that had been successively pretreated with N -methylmaleimide (a trapping reagent of thiols)for 20min and then incubated with PCys-B for 20min resulted in reduced NIR fluores-cence (650–700nm)within cells,whereas strong fluores-cence signals were collected from the cells in the channel of 500–550nm due to the unreacted probe,thus resulting in an increase of the emission ratio to around 1.0.These results imply that PCys-B is a specific probe for Cys and amenable for live cell imaging.

In summary,we designed in this study a fluorescent probe for the detection of Cys with minimal background autofluor-escence,in which two reaction functions,an acrylate ester and an aldehyde,are installed ortho to each other.The reac-tion between the probe and Cys triggers a drastic change of the profile of the fluorescence spectra from a single-peak to a dual-peak profile,which is ascribed to the existence of an excited state intramolecular proton transfer process upon

photo-excitation.As no dual-peak emission spectra profile could be introduced by other related amino acids,we con-clude that PCys-B is a highly selective probe and can monitor Cys with minimum interference from other relevant analytes.More importantly,the ESIPT phototautomer produces an NIR emission with a large Stokes shift,making this probe promising for the selective de-tection of Cys in biological sys-tems by minimizing background

autofluorescence.We further demonstrate that this probe is cell-permeable and can be

used Figure 2.Plot of the fluorescence intensity ratio at 650and 541nm (I 650/I 541)as a function of Cys concentration.R t and R 0represent the fluores-cence intensity ratio I 650/I 541in the presence of different amounts of Cys and in the absence of Cys,respectively.The slope k of the linear regres-sion curve was determined to be 0.257.The standard deviation was deter-mined to be s =2.0 10à3.The detection limit,calculated by the formula (3s /k ),was 2.33 10à7m

.

Figure 3.(a)Fluorescence response of PCys-B (10m m )toward Cys,Hcy,and GSH (100equiv each)after incu-bation at 378C for 20min in acetonitrile/PBS buffer (1:1,v/v,0.01m ,pH 7.2);l ex =527nm.(b)Plots of the

fluorescence intensity ratio (I 650/I 541)of PCys-B (10m m )as a function of time in the presence of Cys,Hcy,and

GSH (100equiv each),respectively;l ex =527

nm.

Figure 4.Fluorescent confocal images of MKN-45cells.(a–d)Cells incu-bated with PCys-B (10m m )for 20min,(a)green fluorescence channel at 500–550nm,(b)red fluorescence channel at 650–700nm,(c)ratio of the images shown in (a)and (b),(d)bright-field image.e–h)Cells pretreated with N -methylmaleimide for 20min prior to incubation with PCys-B (10m m )for 20min,(e)green fluorescence channel at 500–550nm,(f)red fluorescence channel at 650–700nm,(g)ratio of the images shown in (e)and (f),(h)bright-field image.

for Cys imaging in living cells.We anticipate that the strat-egy reported here could be used for designing new specific probes for studying biothiols in complex biological systems.

Experimental Section

Synthesis of PCys-B

Acryloyl chloride(28m L in4mL of CH2Cl2)was added to a solution of3 (100mg,0.23mmol)and Et3N(65m L)in anhydrous CH2Cl2(10mL)at 08C.After stirring for90min at08C,the mixture was warmed to room temperature and further stirred overnight.The solution was then diluted with CH2Cl2(50mL),washed with H2O,and dried over anhydrous Na2SO4.The solvent was removed in vacuo to furnish a crude mixture, which was purified using column chromatography(silica gel,EtOAc/pe-troleum ether1:8)to afford PCys-B(61mg,55%).1H NMR(400MHz, CDCl3):d=1.07(t,3H,),1.45(s,3H),1.68(s,3H),2.37–2.42(q,2H,), 2.74(s,3H),6.10(d,1H),6.40–6.47(m,1H),6.70(d,1H),7.36–7.38(m, 2H),7.55(s,1H),7.59–7.61(m,3H),8.09(s,1H),10.04ppm(s,1H); 13C NMR(100MHz,CDCl

3

):d=188.5,167.5,164.6,150.8,146.3,143.7, 141.7,139.1,137.8,134.4,133.1,131.5,129.7,129.6,128.1,127.5,126.1, 122.4,108.4,30.2,25.1,17.2,13.9,12.4,11.1ppm;HRMS(ESI):calcd for C28H25BF2N2NaO3:509.1824;found:509.1826[M+Na]+.

Acknowledgements

We gratefully acknowledge the financial support by the National Science Foundation of China(grant no.:21172071,21190033,21372083),and the Fundamental Research Funds for the Central Universities.

Keywords:biosensors·biothiols·excited state intramolecular proton transfer·fluorescent probes·imaging agents·NIR emission

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Received:February11,2014

Published online:May7,2014