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

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