Trends in H2S-Donors Chemistry and Their Effects in Cardiovascular Diseases.
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ABSTRACT:
SUBMITTER: Corvino A
PROVIDER: S-EPMC8002049 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hydrogen sulfide (H2S) is an important cellular signaling molecule that exhibits promising protective effects. Although a number of triggerable H2S donors have been developed, spatiotemporal feedback from H2S release in biological systems remains a key challenge in H2S donor development. Herein we report the synthesis, evaluation, and application of caged sulfenyl thiocarbonates as new fluorescent H2S donors. These molecules rely on thiol cleavage of sulfenyl thiocarbonates to release carbonyl sulfide (COS), which is quickly converted to H2S by carbonic anhydrase (CA). This approach is a new strategy in H2S release and does not release electrophilic byproducts common from COS-based H2S releasing motifs. Importantly, the release of COS/H2S is accompanied by the release of a fluorescent reporter, which enables the real-time tracking of H2S by fluorescence spectroscopy or microscopy. Dependent on the choice of fluorophore, either one or two equivalents of H2S 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 H2S 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 H2S-releasing therapeutics. Taken together, sulfenyl thiocarbonates provide a new platform for H2S donation and readily enable fluorescent tracking of H2S delivery in complex environments.
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Project description:Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-?-synthase (CBS), cystathionine-?-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
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Project description:A small library of arylthioamides 1-12 was easily synthesized, and their H2S-releasing properties were evaluated both in the absence or in the presence of an organic thiol such as l-cysteine. A number of arylthioamides (1-3 and 7) showed a slow and l-cysteine-dependent H2S-releasing mechanism, similar to that exhibited by the reference slow H2S-releasing agents, such as diallyl disulfide (DADS) and the phosphinodithioate derivative GYY 4137. Compound 1 strongly abolished the noradrenaline-induced vasoconstriction in isolated rat aortic rings and hyperpolarized the membranes of human vascular smooth muscle cells in a concentration-dependent fashion. Finally, a significant reduction of the systolic blood pressure of anesthetized normotensive rats was observed after its oral administration. Altogether these results highlighted the potential of arylthioamides 1-3 and 7 as H2S-donors for basic studies, and for the rational design/development of promising pharmacotherapeutic agents to treat cardiovascular diseases.
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