Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure-activity study

Ana S. Newton, Paulo M.C. Glória, Lídia M. Gonalves, Daniel J.V.A. Dos Santos, Rui Moreira, Rita C. Guedes, Maria M.M. Santos

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp at P1, as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CHCH-SO 2Me was the most potent inhibitor of caspase-3 in the series, with a IC50 of 29 μM and a second-order rate constant of inactivation, kinact/Ki, of 1.5 M-1 s-1. Computational studies suggest that the second amino acid occupies position S3 of the enzyme. In addition, Fmoc-Val-Asp-trans-CHCH-SO 2Ph was inactive for caspase-7 for the tested concentrations. The first structure-activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for caspase-3 inhibition.

Original languageEnglish
Pages (from-to)3858-3863
Number of pages6
JournalEuropean Journal of Medicinal Chemistry
Volume45
Issue number9
DOIs
Publication statusPublished - Sept 2010
Externally publishedYes

Keywords

  • Caspase-3 inhibitor
  • Irreversible inhibitor
  • Michael acceptor
  • Vinyl sulfone

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