LAUSR

Hydrogen sulfide (H2S) is an important signaling molecule that provides protective activities in a variety of physiological and pathological processes. Among the different types of H2S donor compounds, thioamides have attracted attention due to prior conjugation to non-steroidal anti-inflammatory drugs (NSAIDs) to access H2S-NSAID hybrids with significantly-reduced tox-icity, but the mechanism of H2S release from thioamides remains unclear. Herein, we reported the synthesis and evaluation of a class of thioamide-derived sulfenyl thiocarbamates (SulfenylTCMs) that function as a new class of H2S donors. These com-pounds are efficiently activated by cellular thiols to release carbonyl sulfide (COS), which is quickly converted to H2S by car-bonic anhydrase (CA). In addition, through mechanistic investigations we establish that COS-independent H2S release path-ways are also operative. In contrast to the parent thioamide-based donors, the SulfenylTCMs exhibit excellent H2S releasing efficiencies of up to 90% and operate through mechanistically well-defined pathways. In addition, we demonstrate that the sulfenyl thiocarbamate group is readily attached to common NSAIDs, such as naproxen, to generate YZ-597 as an efficient H2S-NSAID hybrid, which we demonstrate releases H2S in cellular environments. Taken together, this new class of H2S donor motifs provide an important platform for new donor development.