Total synthesis and absolute stereochemistry of the proteasome inhibitors cystargolides A and B

Org Biomol Chem. 2015 Oct 28;13(40):10127-30. doi: 10.1039/c5ob01821h. Epub 2015 Sep 24.

Abstract

The absolute stereochemistry of the cystargolides was determined by total synthesis. Evaluation of synthetic cystargolides and derivatives showed that the natural (2S,3R) stereochemistry is essential for activity. Moreover, benzyl esters (-)-10 and (-)-15 were found to be about 100 times more potent, and to selectively kill MCF-7 cancerous cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Proliferation / drug effects
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • MCF-7 Cells
  • Molecular Conformation
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemical synthesis*
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Proteasome Inhibitors
  • cystargolide A
  • cystargolide B
  • Proteasome Endopeptidase Complex