The first structure–activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P1, as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH=CH–SO2Me was the most potent inhibitor of caspase-3 in the series, with a IC50 of 29 μM and a second-order rate constant of inactivation, kinact/Ki, of 1.5 M−1 s−1. Computational studies suggest that the second amino acid occupies position S3 of the enzyme. In addition, Fmoc-Val-Asp-trans-CH=CH–SO2Ph was inactive for caspase-7 for the tested concentrations.
Ana S. Newton, Paulo M.C. Glória, Lídia M. Gonçalves, Daniel J.V.A. dos Santos, Rui Moreira, Rita C. Guedes, Maria M.M. Santos
Medicinal Chemistry, iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019 Lisboa, Portugal