Intramolecular Thiol‐ and Selenol‐Assisted Delivery of Hydrogen Sulfide

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. Although aryl thioamides are often used to assess the pharmacological effects of H2S, their reactivity is extremely sluggish and their release of H2S is highly inefficient. Herein, we report that H2S liberation from this donor class can be augmented with intramolecular nucleophilic assistance. We envision this new chemistry serving as a general design strategy for accessing efficient donors that selectively respond to various biological stimuli.