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

In this article we describe an expanded structureeactivity 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 log P 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.

Keywords

Vinyl sulfone Caspase-3 inhibitor Michael acceptor Irreversible inhibitor Yeast cell-based assay

URI

http://dx.doi.org/10.1016/j.ejmech.2011.02.067
http://hdl.handle.net/10451/3843

Citation

Paulo M. C. Glória; Coutinho, I; Lídia M. Gonçalves; Baptista, C; Soares, J; Ana S. Newton; Moreira, R; Saraiva, L; Santos, Maria Manuel Duque Vieira Marques dos. Aspartic vinyl sulfones: inhibitors of a caspase-3-dependent pathway, European Journal of Medicinal Chemistry, 46, 2141-2146, 2011.