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

Hydrogen sulfide (H(2)S) is an important signaling molecule that provides protective activities in a variety of physiological and pathological processes. Among the different types of H(2)S donor compounds, thioamides have attracted attention due to prior conjugation to non-steroidal anti-inflammatory drugs (NSAIDs) to access H(2)S-NSAID hybrids with significantly-reduced toxicity, but the mechanism of H(2)S 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 H(2)S donors. These compounds are efficiently activated by cellular thiols to release carbonyl sulfide (COS), which is quickly converted to H(2)S by carbonic anhydrase (CA). In addition, through mechanistic investigations we establish that COS-independent H(2)S release pathways are also operative. In contrast to the parent thioamide-based donors, the SulfenylTCMs exhibit excellent H(2)S 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 H(2)S-NSAID hybrid, which we demonstrate releases H(2)S in cellular environments. Taken together, this new class of H(2)S donor motifs provide an important platform for new donor development.