Aspartic vinyl sulfones: Inhibitors of a caspase-3-dependent pathway

In this article we describe an expanded structure–activity relationship study for vinyl sulfones as caspase-3 inhibitors, a topic virtually unexplored in the existing literature. Most remarkably, and to our surprise, tripeptidyl vinyl sulfones were not active for caspase-3, opposite to other examples described in literature for peptidyl vinyl sulfones as potent cysteine protease inhibitors of clan CA. Moreover, the caspase-3 inhibitory activity of vinyl sulfones using an in vitro assay was then confirmed using a yeast cell-based assay. The results show that Fmoc-protected vinyl sulfones containing only the Asp moiety are inhibitors of a caspase-3-dependent pathway and the IC50 values obtained in the yeast assay are in the same order of magnitude of that obtained with the caspase-3 inhibitor tetrapeptidyl chloromethyl ketone, Ac-DEVD-CMK. This observation is consistent with appropriate cell permeability properties displayed by the vinyl sulfone inhibitors, as reflected by logP values ranging from 1.1 to 3.4. Overall, these results suggest that vinyl sulfones containing Asp at P1 should be considered for further optimization as caspase inhibitors and modulators of caspase-3-dependent pathways. A series of peptidyl vinyl sulfones were synthesized and screened for caspase-3 inhibition using in vitro and yeast cell-based assays. [Display omitted] ► Synthesis of dipeptidyl and tripeptidyl vinyl sulfones containing Asp at P1. ► SAR study of vinyl sulfone scaffold for caspase inhibitors. ► Yeast caspase-3 cell-based assay to screen synthetic caspase-3 inhibitors.