Papers of the Week

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the frontline treatments for inflammation and pain. Hydrogen sulfide (HS) 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-HS hybrids, where a strategic placement of a sulfhydryl group adjacent to a carbonyl of a NSAID facilitates the enzymatic generation of HS. 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 HS 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 HS. 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 HS 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 HS. 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 HS 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 HS presents new opportunities to enhance the properties of NSAIDs through participation in endogenous HS biosynthesis.