A highly selective sulfinate ester probe for thiol bioimaging

Malwal, Satish R.; Labade, Ajay S.; Andhalkar, Abhijeet S.; Sengupta, Kundan; Chakrapani, Harinath

doi:10.1039/c4cc05462h

Cited by 40 publications

(26 citation statements)

References 27 publications

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“…Because the intensity of the light generated directly correlates to the amount of liberated d ‐luciferin, it would serve as an indicator of thiol activity. The tert ‐butyl sulfinate ester was selected as the caging group, considering that its selective cleavage by thiols owing to its thiophilicity had been previously reported …”

Section: Resultsmentioning

confidence: 99%

“…By combining the two components, we designed SEluc‐1 and SEluc‐2 as shown in Scheme . Both the caging group of SEluc‐1 and d ‐luciferin were synthesized as previously reported . Initial attempts to synthesize SEluc‐1 by attaching the ligand to 2‐cyano‐6‐hydroxybenzothiazole, followed by a coupling reaction with d ‐cysteine, proved futile as the addition of d ‐cysteine resulted in the immediate cleavage of the ligand.…”

Section: Resultsmentioning

confidence: 99%

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Highly Sensitive Bioluminescent Probe for Thiol Detection in Living Cells

Hemmi

Ikeda

Shindo

et al. 2018

Chemistry An Asian Journal

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The sensitive detection of thiols including glutathione and cysteine is desirable owing to their roles as indispensable biomolecules in maintaining intracellular biological redox homeostasis. Herein, we report the design and synthesis of SEluc-1 (sulfinate ester luciferin), a chemoselective probe exhibiting a ratiometric and turn-on response towards thiols selectively in fluorescence and bioluminescence, respectively. The probe, which was designed based on the "caged" luciferin strategy, displays excellent selectivity, high signal/noise ratio (>240 in the case of bioluminescence), and a biologically relevant limit of detection (LOD, 80 nm for cysteine), which are all desirable traits for a sensitive bioluminescent sensor. SEluc-1 was further applied to fluorescence imaging of thiol activity in living human cervical cancer HeLa cell cultures, and was successfully able to detect fluctuations in thiol concentrations induced by oxidative stress in a bioluminescent assay utilizing African green monkey fibroblast COS-7 cells and human breast adenocarcinoma MCF-7 cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Highly Sensitive Bioluminescent Probe for Thiol Detection in Living Cells

Hemmi

Ikeda

Shindo

et al. 2018

Chemistry An Asian Journal

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“…In this study, we present the synthesis of the 2,4‐dinitrobenzenesulfinate (DNBS) derivative of GG, that is, DNBS‐GG, a new sulfinate‐based23 biothiol‐sensitive group based on such a selective thiolysis reaction. This compound presents an excellent performance in terms of avoiding undesirable hydrolysis reactions, thus increasing the specificity of the fluorogenic probe toward biothiols.…”

Section: Introductionmentioning

confidence: 99%

New Dual Fluorescent Probe for Simultaneous Biothiol and Phosphate Bioimaging

Resa

Orte

Miguel

et al. 2015

Chemistry A European J

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The simultaneous detection of relevant metabolites in living organisms by using one molecule introduces an approach to understanding the relationships between these metabolites in healthy and deregulated cells. Fluorescent probes of low toxicity are remarkable tools for this type of analysis of biological systems in vivo. As a proof of concept, different naturally occurring compounds, such as biothiols and phosphate anions, were the focus for this work. The 2,4-dinitrobenzenesulfinate (DNBS) derivative of 9-[1-(4-tert-butyl-2-methoxyphenyl)]-6-hydroxy-3H-xanthen-3-one (Granada Green; GG) were designed and synthesized. This new sulfinyl xanthene derivative can act as a dual sensor for the aforementioned analytes simultaneously. The mechanism of action of this derivative implies thiolysis of the sulfinyl group of the weakly fluorescent DNBS-GG by biological thiols at near-neutral pH values, thus releasing the fluorescent GG moiety, which simultaneously responds to phosphate anions through its fluorescence-decay time. The new dual probe was tested in solution by using steady-state and time-resolved fluorescence and intracellularly by using fluorescence-lifetime imaging microscopy (FLIM) in human epithelioid cervix carcinoma (HeLa) cells.

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“…Looking to the literature, this result was not all that surprising as sulfinic esters are known to be highly selective toward nucleophilic substitution by thiols. (19) Although this lends little information on specific protein target(s), we still viewed this as valuable knowledge where a thiol/cysteine could be involved in the ester cleavage event, assuming that 6 and 23 share a common protein target. Placing these findings in context, we note quinone methide precursor mastery seen in the seminal publications by Danzin, Widlanski, and others.…”

Section: Resultsmentioning

confidence: 99%

“…The sensitivity of the sulfinic ester moiety toward glutathione (GSH), a universal cellular component, has been reported. (19)Hence, we conducted MS-based stability studies on 6 and 23 in various medium using deuterium-labeled compounds as standards. While both 6 and 23 displayed similar stability in PBS and culture medium (see the Supporting Information), a significant difference was observed in 5 mM GSH solution.…”

Section: Resultsmentioning

confidence: 99%

Cellular Protection of SNAP-25 against Botulinum Neurotoxin/A: Inhibition of Thioredoxin Reductase through a Suicide Substrate Mechanism

Seki¹,

Xue²,

Pellett

et al. 2016

J. Am. Chem. Soc.

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Botulium neurotoxins (BoNTs) are among the most lethal toxins known to man. They are comprised of seven serotypes with BoNT/A being the most deadly; yet, there is no approved therapeutic for their intoxication or one that has even advanced to clinical trials. Botulinum neurotoxicity is ultimately governed through light chain (LC) protease SNARE protein cleavage leading to a loss of neurotransmitter release. Pharmacological attempts to ablate BoNT/A intoxication have sought to either nullify cellular toxin entry or critical biochemical junctions found within its intricate mechanism of action. In these regards, reports have surfaced of nonpeptidic small molecule inhibitors, but few have demonstrated efficacy in neutralizing cellular toxicity, a key prerequisite before rodent lethality studies can be initiated. On the basis of a lead discovered in our BoNT/A cellular assay campaign, we investigated a family of N-hydroxysuccinimide inhibitors grounded upon structure activity relationship (SAR) fundamentals. Molecules stemming from this SAR exercise were theorized to be protease inhibitors. However, this proposition was overturned on the basis of extensive kinetic analysis. Unexpectedly, inhibitor data pointed to thioredoxin reductase (TrxR), an essential component required for BoNT protease translocation. Also unforeseen was the inhibitors’ mechanism of action against TrxR, which was found to be brokered through a suicide-mechanism utilizing quinone methide as the inactivating element. This new series of TrxR inhibitors provides an alternative means to negate the etiological agent responsible for BoNT intoxication, the LC protease.

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A highly selective sulfinate ester probe for thiol bioimaging

Abstract: We describe here hitherto unexplored chemistry of the sulfinate ester functional group as being highly selective towards nucleophilic substitution by thiols at physiological pH. Using this cleavable trigger, an optical thiol probe that is suitable for thiol bioimaging has been developed.

Cited by 40 publications

References 27 publications

Highly Sensitive Bioluminescent Probe for Thiol Detection in Living Cells

Highly Sensitive Bioluminescent Probe for Thiol Detection in Living Cells

New Dual Fluorescent Probe for Simultaneous Biothiol and Phosphate Bioimaging

Cellular Protection of SNAP-25 against Botulinum Neurotoxin/A: Inhibition of Thioredoxin Reductase through a Suicide Substrate Mechanism

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