Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/HS Donors.

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