Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H<sub>2</sub>S Donors

Hydrogen sulfide (H<sub>2</sub>S) is an important biological mediator, and synthetic H<sub>2</sub>S donating molecules provide an important class of investigative tools for H<sub>2</sub>S research. Here, we report esterase-activated H<sub>2</sub>S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H<sub>2</sub>S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H<sub>2</sub>S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H<sub>2</sub>S donors exhibit higher levels of cytotoxicity than equivalent levels of Na<sub>2</sub>S or the common H<sub>2</sub>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/H<sub>2</sub>S inhibition of cytochrome c oxidase in the mitochondrial respiratory chain although not observed with common H<sub>2</sub>S donors at the same concentrations. Taken together, these results may suggest that COS functions differently than H<sub>2</sub>S in certain biological contexts or that the developed donors are more efficient at delivering H<sub>2</sub>S than other common H<sub>2</sub>S-releasing motifs.