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|Title: ||Aspartic vinyl sulfones: inhibitors of a caspase-3-dependent pathway|
|Authors: ||Glória, Paulo M. C.|
Gonçalves, Lídia M.
Newton, Ana S.
Santos, Maria M. M.
|Keywords: ||Vinyl sulfone|
Yeast cell-based assay
|Issue Date: ||2011|
|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.|
|Abstract: ||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.|
|Peer Reviewed: ||yes|
|Publisher version: ||http://www.sciencedirect.com/science/article/pii/S0223523411001954|
|Appears in Collections:||FF-DQFT - Artigos em Revistas Internacionais|
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