Use of Dithiasuccinoyl-Caged Amines Enables COS/H2S Release Lacking Electrophilic Byproducts

M. M. Cerda, J. L. Mancuso, E. J. Mullen, C. H. Hendon, M. D. Pluth
Chemistry-A European Journal
Volume 26, Issue 24, Page 5374-5380
Published while none of the authors were employed at the CMM


The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H2S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H2S 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 H2S 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/H2S donor motifs, and that these groups release two equivalents of COS/H2S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H2S 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.