Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H₂S Donors

Hydrogen sulfide (H₂S) is an important biological mediator, and synthetic H₂S donating molecules provide an important class of investigative tools for H₂S research. Here, we report esterase-activated H₂S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H₂S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H₂S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H₂S donors exhibit higher levels of cytotoxicity than equivalent levels of Na₂S or the common H₂S donors GYY4137 and AP39. Using cellular bioenergetics measurements, we establish that the developed donors reduce cellular respiration and ATP synthesis in BEAS 2B human lung epithelial cells, which is consistent with COS/H₂S inhibition of cytochrome c oxidase in the mitochondrial respiratory chain although not observed with common H₂S donors at the same concentrations. Taken together, these results may suggest that COS functions differently than H₂S in certain biological contexts or that the developed donors are more efficient at delivering H₂S than other common H₂S-releasing motifs.