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

Eur J Med Chem. 2010 Sep;45(9):3858-63. doi: 10.1016/j.ejmech.2010.05.039. Epub 2010 May 24.

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 P(1), as caspase-3 inhibitors. Fmoc-Val-Asp-trans-CH=CH-SO(2)Me was the most potent inhibitor of caspase-3 in the series, with a IC(50) of 29 microM and a second-order rate constant of inactivation, k(inact)/K(i), of 1.5 M(-1) s(-1). Computational studies suggest that the second amino acid occupies position S(3) of the enzyme. In addition, Fmoc-Val-Asp-trans-CH=CH-SO(2)Ph was inactive for caspase-7 for the tested concentrations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 3 / chemistry
  • Caspase Inhibitors*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Protein Conformation
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry*
  • Sulfones / pharmacology*

Substances

  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Sulfones
  • divinyl sulfone
  • Caspase 3