Use of Dithiasuccinoyl-Caged Amines Enables COS/H2 S Release Lacking Electrophilic Byproducts.

The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H2 S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H2 S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS-based H2 S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H2 S donor motifs, and that these groups release two equivalents of COS/H2 S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H2 S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.