Enantio- and diastereoselective total synthesis of EI-1941-1, -2, and -3, inhibitors of interleukin-1beta converting enzyme, and biological properties of their derivatives

J Org Chem. 2005 Nov 25;70(24):9905-15. doi: 10.1021/jo0516436.

Abstract

[reaction: see text] The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1beta converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode followed by beta-hydride elimination. The investigation of the biological properties of EI-1941-1, -2, and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less cytotoxicity than EI-1941-1 and -2 in a cultured cell system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase Inhibitors*
  • Cell Line
  • Cell Survival / drug effects
  • Cyclohexanones / chemical synthesis*
  • Cyclohexanones / chemistry
  • Cyclohexanones / pharmacology*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epoxy Compounds / chemical synthesis*
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology*
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Molecular Conformation
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Caspase Inhibitors
  • Cyclohexanones
  • EI-1941-1
  • EI-1941-2
  • EI-1941-3
  • Enzyme Inhibitors
  • Epoxy Compounds
  • Heterocyclic Compounds, 2-Ring