Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H 2 S Donors.

Hydrogen sulfide (H2 S) is an important biological mediator, and synthetic H2 S donating molecules provide an important class of investigative tools for H2 S research. Here, we report esterase-activated H2 S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H2 S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H2 S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H2 S donors exhibit higher levels of cytotoxicity than equivalent levels of Na2 S or the common H2 S 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/H2 S inhibition of cytochrome c oxidase in the mitochondrial respiratory chain although not observed with common H2 S donors at the same concentrations. Taken together, these results may suggest that COS functions differently than H2 S in certain biological contexts or that the developed donors are more efficient at delivering H2 S than other common H2 S-releasing motifs.