Cyclic Sulfenyl Thiocarbamates Release Carbonyl Sulfide and Hydrogen Sulfide Independently in Thiol-Promoted Pathways

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 nonsteroidal anti-inflammatory drugs (NSAIDs) to access H₂S-NSAID hybrids with significantly reduced toxicity, 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 compounds are efficiently activated by cellular thiols to release carbonyl sulfide (COS), which is quickly converted to H₂S by carbonic anhydrase (CA). In addition, through mechanistic investigations, we establish that COS-independent H₂S release pathways 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 provides an important platform for new donor development.