Cyclic Sulfenyl Thiocarbamates Release Carbonyl Sulfide and Hydrogen Sulfide Independently in Thiol-Promoted Pathways
Year: 2019
Type: article
Abstract: 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 nonsteroidal 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 provides an important platform for new donor development.
DOI: 10.1021/jacs.9b06319
Authors: Yu Zhao, Andrea K. Steiger, Michael D. Pluth
Institution: University of Oregon
Language: English
Topic: Sulfur Compounds in Biology
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2964925364