Development of Acid-Mediated H2S/COS Donors That Respond to a Specific pH Window

Hydrogen sulfide (H2S) is a biologically relevant molecule, and recent efforts have focused on developing small molecular donors that deliver H2S on demand. Acid-activated donors have garnered significant interest due to the potential application of such systems in myocardial ischemia injury or for suppressing tumor growth. In this work, we report a new strategy for tuning H2S delivery to a specific pH window. Specifically, we utilize self-immolative thiocarbamates with an imine-derived triggering group. After imine hydrolysis, the self-immolative decomposition releases carbonyl sulfide (COS), which is quickly hydrolyzed to H2S by carbonic anhydrase. Although acid-mediated hydrolysis results in imine cleavage, environments that are too acidic result in protonation of the aniline intermediate and results in inhibition of COS/H2S release. Taken together, this mechanism enables access to donor motifs that are only activated within specific pH windows. Here, we demonstrate the design, preparation, and pH evaluation of a series of imine-based COS/H2S donor motifs, which we anticipate that will have utility in investigating H2S in acidic microenvironments.