Harnessing Hydrogen Cyanide (HCN): Responsive Chemical Tools for Delivering an Emerging Gasotransmitter

Abstract Hydrogen cyanide (HCN) is an emerging gasotransmitter, joining NO, CO, and H 2 S in a group of important endogenous signaling and regulatory molecules. Despite this importance, synthetic HCN donors that respond to broadly tunable stimuli remain absent. Here, I report a platform approach for developing synthetic HCN donors that can be tuned to release HCN on demand in response to endogenous stimuli. The reported donors are stable in solution until activated by a specific stimulus, in this case esterases, after which they release a caged cyanohydrin that is spontaneously hydrolyzed in water to generate HCN. This approach is also compatible with responsive self‐immolative 1,6‐elimination platforms, allowing for significant modification of release rates, while providing a general, modular, and tunable platform for HCN delivery in response to specific stimuli. Moreover, the developed donors are shown to release HCN in live cells, thereby significantly advancing the available approaches for HCN delivery in complex environments.