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

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 non-steroidal antiinflammatory 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.

Trends in H2S-Donors Chemistry and Their Effects in Cardiovascular Diseases

“…Thus, in order to obtain effective H 2 S donors with controllable release rates, a series of N-(benzoylthio)benzamides [ 49 ], acyl perthiols [ 50 , 51 ], arylthioamides [ 52 ], 1,2,4-thiadiazolidin-3,5-diones [ 53 ], iminothioethers [ 54 ], mercaptopyruvate [ 55 ], dithioates [ 56 ], isothiocyanate [ 57 , 58 ], and thiocarbamates [ 59 ] were developed and evaluated for their H 2 S-releasing properties.…”

Current Trends and Future Perspectives of Hydrogen Sulfide Donors

“…These compounds in presence of cellular thiols generate carbonyl sulfide (COS) followed by the release of H2S by carbonic anhydrase (CA) [90] (Figure 13). The stable-dithiol-based-H2S Donors are obtained by the addition of a photolabile 2-nitrobenzyl group for protection of SH group.…”

A Dinuclear Persulfide‐Bridged Ruthenium Compound is a Hypoxia‐Selective Hydrogen Sulfide (H2S) Donor

“…The implementation of H 2 S in medicine, however, is limited by its gaseous nature, flammability, and toxicity at high concentrations. As such, significant research efforts have focused on developing easily handled prodrugs for this gaseous molecule [4–12] . Simple sulfide salts such as Na 2 S or NaSH rapidly release H 2 S upon dissolution in aqueous solution.…”

“…As such, significant research efforts have focused on developing easily handled prodrugs for this gaseous molecule. [4][5][6][7][8][9][10][11][12] Simple sulfide salts such as Na 2 S or NaSH rapidly release H 2 S upon dissolution in aqueous solution. Although these complexes are more practical for the delivery of H 2 S than its direct administration as a gas, their rapid release profiles do not mimic endogenous H 2 S production and often elicit toxic side effects.…”