Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification

Bioorg Med Chem Lett. 2013 Feb 1;23(3):733-6. doi: 10.1016/j.bmcl.2012.11.087. Epub 2012 Dec 5.

Abstract

Chaetocin (1), a structurally complex epidithiodiketopiperazine (ETP) alkaloid produced by Chaetomium minutum, is a potent inhibitor of protein lysine methyltransferase G9a, which plays important roles in many biological processes. Here we present our synthetic investigations to identify a simple prototype G9a inhibitor structure based on structure-activity relationship (SAR) studies on chaetocin derivatives. The simple derivative PS-ETP-1 (14) was found to be a potent G9a inhibitor with greatly reduced cytotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • Chaetomium / chemistry*
  • Diketopiperazines / chemical synthesis*
  • Diketopiperazines / chemistry
  • Diketopiperazines / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • HL-60 Cells
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Humans
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Structure-Activity Relationship
  • Thioredoxin-Disulfide Reductase / metabolism

Substances

  • Diketopiperazines
  • Enzyme Inhibitors
  • Piperazines
  • chaetocin
  • Thioredoxin-Disulfide Reductase
  • Histone-Lysine N-Methyltransferase