Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure-activity study

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 P(1), as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH=CH-SO(2)Me was the most potent inhibitor of caspase-3 in the series, with a IC(50) of 29 microM and a second-order rate constant of inactivation, k(inact)/K(i), of 1.5 M(-1) s(-1). Computational studies suggest that the second amino acid occupies position S(3) of the enzyme. In addition, Fmoc-Val-Asp-trans-CH=CH-SO(2)Ph was inactive for caspase-7 for the tested concentrations.