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

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• 作者：Paulo M.C. Gl&#xf3 ; ria ; Isabel Coutinho ; Lí ; dia M. Gonç ; alves ; Cristina Baptista ; Joana Soares ; Ana S. Newton ; Rui Moreira ; Lucí ; lia Saraiva ; Maria M.M. Santos
• 关键词：Vinyl sulfone ; Caspase-3 inhibitor ; Michael acceptor ; Irreversible inhibitor ; Yeast cell-based assay
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：46
• 期：6
• 页码：2141-2146
• 全文大小：298 K

文摘

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 P₁ should be considered for further optimization as caspase inhibitors and modulators of caspase-3-dependent pathways.