Moving Past Quinone-Methides: Recent Advances Toward Minimizing Electrophilic Byproducts from COS/H₂S Donors

Hydrogen sulfide (H₂S) is an important biomolecule that plays key signaling and protective roles in different physiological processes. With goals of advancing both the available research tools and the associated therapeutic potential of H₂S, researchers have developed different methods to deliver H₂S on demand in different biological contexts. A recent approach to develop such donors has been to design compounds that release carbonyl sulfide (COS), which is quickly converted to H₂S in biological systems by the ubiquitous enzyme carbonic anhydrase (CA). Although highly diversifiable, many approaches using this general platform release quinone methides or related electrophiles after donor activation. Many such electrophiles are likely scavenged by water, but recent efforts have also expanded alternative approaches that minimize the formation of electrophilic byproducts generated after COS release. This mini-review focuses specifically on recent examples of COS-based H₂S donors that do no generate quinone methide byproducts after donor activation.