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Abstract Hydrogen sulfide (H2S) is a biologically active molecule that exhibits protective effects in a variety of physiological and pathological processes. Although several H2S‐related biological effects have been discovered by using H2S donors, knowing how much H2S has been released from donors under different conditions remains challenging. Now, a series of γ‐ketothiocarbamate (γ‐KetoTCM) compounds that provide the first examples of colorimetric H2S donors and enable direct quantification of H2S release, were reported. These compounds are activated through a pH‐dependent deprotonation/β‐elimination sequence to release carbonyl sulfide (COS), which is quickly converted into H2S by carbonic anhydrase. Thep‐nitroaniline released upon donor activation provides an optical readout that correlates directly to COS/H2S release, thus enabling colorimetric measurement of H2S donation.
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Enol-Mediated Delivery of H 2 Se from γ-Keto Selenides: Mechanistic Insight and Evaluation
Similar to hydrogen sulfide (H 2 S), its chalcogen congener, Hydrogen selenide (H 2 Se), is an emerging molecule of interest given its endogenous expression and purported biological activity. However, unlike H 2 S, detailed investigations into the chemical biology of H 2 Se are limited and little is known about its innate physiological functions, cellular targets, and therapeutic potential. The obscurity surrounding these fundamental questions is largely due to a lack of small molecule donors that can effectively increase the bioavailability of H 2 Se through their continuous liberation of the transient biomolecule under physiologically relevant conditions. Driven by this unmet demand for H 2 Se-releasing moieties, we report that γ-keto selenides provide a useful platform for H 2 Se donation via an α-deprotonation/β-elimination pathway that is highly dependent on both pH and alpha proton acidity. These attributes afforded a small library of donors with highly variable rates of release (higher alpha proton acidity = faster selenide liberation), which is accelerated under neutral to slightly basic conditions—a feature that is unique and complimentary to previously reported H 2 Se donors. We also demonstrate the impressive anticancer activity of γ-keto selenides in both HeLa and HCT116 cells in culture, which is likely to stimulate additional interest and research into the biological activity and anticancer effects of H 2 Se. Collectively, these results indicate that γ-keto selenides provide a highly versatile and effective framework for H 2 Se donation.
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- Award ID(s):
- 2143826
- PAR ID:
- 10377799
- Date Published:
- Journal Name:
- Chemical Science
- ISSN:
- 2041-6520
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Hydrogen sulfide (H 2 S) is an important cellular signaling molecule that exhibits promising protective effects. Although a number of triggerable H 2 S donors have been developed, spatiotemporal feedback from H 2 S release in biological systems remains a key challenge in H 2 S donor development. Herein we report the synthesis, evaluation, and application of caged sulfenyl thiocarbonates as new fluorescent H 2 S donors. These molecules rely on thiol cleavage of sulfenyl thiocarbonates to release carbonyl sulfide (COS), which is quickly converted to H 2 S by carbonic anhydrase (CA). This approach is a new strategy in H 2 S release and does not release electrophilic byproducts common from COS-based H 2 S releasing motifs. Importantly, the release of COS/H 2 S is accompanied by the release of a fluorescent reporter, which enables the real-time tracking of H 2 S by fluorescence spectroscopy or microscopy. Dependent on the choice of fluorophore, either one or two equivalents of H 2 S can be released, thus allowing for the dynamic range of the fluorescent donors to be tuned. We demonstrate that the fluorescence response correlates directly with quantified H 2 S release and also demonstrate the live-cell compatibility of these donors. Furthermore, these fluorescent donors exhibit anti-inflammatory effects in RAW 264.7 cells, indicating their potential application as new H 2 S-releasing therapeutics. Taken together, sulfenyl thiocarbonates provide a new platform for H 2 S donation and readily enable fluorescent tracking of H 2 S delivery in complex environments.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D2SC03533B
