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Hydrogen sulfide (H2S) is an endogenous signaling molecule that greatly influences several important (patho)physiological processes related to cardiovascular health and disease, including vasodilation, angiogenesis, inflammation, and cellular redox homeostasis. Consequently, H2S supplementation is an emerging area of interest, especially for the treatment of cardiovascular-related diseases. To fully unlock the medicinal properties of hydrogen sulfide, however, the development and refinement of H2S releasing compounds (or donors) are required to augment its bioavailability and to better mimic its natural enzymatic production. Categorizing donors by the biological stimulus that triggers their H2S release, this review highlights the fundamental chemistry and releasing mechanisms of a range of H2S donors that have exhibited promising protective effects in models of myocardial ischemia-reperfusion (MI/R) injury and cancer chemotherapy-induced cardiotoxicity, specifically. Thus, in addition to serving as important investigative tools that further advance our knowledge and understanding of H2S chemical biology, the compounds highlighted in this review have the potential to serve as vital therapeutic agents for the treatment (or prevention) of various cardiomyopathies. 

Abstract Arylthioamides have been frequently employed to assess the chemical biology and pharmacology of hydrogen sulfide (H₂S). From this class of donors, however, extremely low H₂S releasing efficiencies have been reported and proper mechanistic studies have been omitted. Consequently, millimolar concentrations of arylthioamides are required to liberate just trace amounts of H₂S, and via an unidentified mechanistic pathway, which obfuscates the interpretation of any biological activity that stems from their use. Herein, we report that H₂S release from this valuable class of donors can be markedly enhanced through intramolecular nucleophilic assistance. Specifically, we demonstrate that both disulfide‐ and diselenide‐linked thioamides are responsive to biologically relevant concentrations of glutathione and release two molar equivalents of H₂S via an intramolecular cyclization that significantly augments their rate and efficiency of sulfide delivery in both buffer and live human cells.