Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 46, Issue 6, Pages 2141-2146Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.02.067
Keywords
Vinyl sulfone; Caspase-3 inhibitor; Michael acceptor; Irreversible inhibitor; Yeast cell-based assay
Categories
Funding
- Fundacao para a Ciencia e Tecnologia (Lisbon, Portugal) [SFRH/BD/36066/2007, SFRH/BD/41276/2007]
- REQUIMTE/CEQUP, FCT [8/94]
- POCTI
- FEDER
- Universidade do Porto/Santander Totta
- Fundação para a Ciência e a Tecnologia [SFRH/BD/41276/2007, SFRH/BD/36066/2007] Funding Source: FCT
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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 log P values ranging from 1.1 to 3.4. Overall, these results suggest that vinyl sulfones containing Asp at P-1 should be considered for further optimization as caspase inhibitors and modulators of caspase-3-dependent pathways. (C) 2011 Elsevier Masson SAS. All rights reserved.
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