Esterase-Triggered Self-Immolative Thiocarbamates Provide Insights into COS Cytotoxicity.

Hydrogen sulfide (HS) is an important gasotransmitter and biomolecule, and many synthetic small-molecule HS donors have been developed for HS-related research. One important class of triggerable HS donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to HS by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than HS. Here, we report a suite of modular esterase-triggered self-immolative COS donors and include the synthesis, HS release profiles, and cytotoxicity of the developed donors. We demonstrate that the rate of ester hydrolysis correlates directly with the observed cytotoxicity in cell culture, which further supports the hypothesis that COS functions as more than a simple HS shuttle in certain biological systems.