Mercapto-NSAIDs generate a non-steroidal anti-inflammatory drug (NSAID) and hydrogen sulfide

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the frontline treatments for inflammation and pain. Hydrogen sulfide (H2S) and related persulfide (RS-SH) are important mediators of antioxidant response and protect cells from oxidative stress. Hybrids of these pharmacological agents have shown promise in clinical trials and are superior to the parent NSAID. Here, we report a new class of NSAID–H2S hybrids, where a strategic placement of a sulfhydryl group adjacent to a carbonyl of a NSAID facilitates the enzymatic generation of H2S. We show that α-mercapto-nabumetone, a derivative of the clinical drug nabumetone, is a substrate for 3-mercaptopyruvate sulfurtransferase (3-MST), an enzyme involved in H2S biosynthesis. The key step of 3-MST catalysis is the cleavage of a C–S bond adjacent to a carbonyl group, which generates an enolate and 3-MST persulfide, which in turn is cleaved under reducing conditions to generate H2S. Guided by a molecular docking study with 3-MST, we prepared two mercapto-nabumetone derivatives, protected as their thioacetates. In the presence of 3-MST, both mercapto-nabumetone derivatives generated H2S and the NSAID in a nearly quantitative yield, produced glutathione persulfide (GS-SH), an important mediator of cellular antioxidant response, and permeated cells to generate H2S. Lastly, to gain insights into the scope of this strategy, we prepared mercapto-NSAID derivatives containing a carboxylic acid. We found that the propensity to generate H2S depended on the nature of the enol that is produced during the transformation of the mercapto-NSAID into the parent NSAID. This offers new insights into 3-MST catalysis and how reaction outcomes can be modulated by the keto–enol equilibrium. Taken together, the atom economical transformation of a clinical NSAID with one strategically placed sulfhydryl group to generate H2S presents new opportunities to enhance the properties of NSAIDs through participation in endogenous H2S biosynthesis.