Synthesis, biological evaluation, and molecular docking of Ugi products containing a zinc-chelating moiety as novel inhibitors of histone deacetylases

J Med Chem. 2009 May 14;52(9):2776-85. doi: 10.1021/jm801529c.

Abstract

HDAC inhibitors show great promise for the treatment of cancer. As part of a broader effort to explore the SAR of HDAC inhibitors, synthesis, biological evaluation, and molecular docking of novel Ugi products containing a zinc-chelating moiety are presented. One compound shows improved inhibitory potencies compared to SAHA, demonstrating that hindered lipophilic residues grafted on the peptide scaffold of the alpha-aminoacylamides can be favorable in the interaction with the enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemistry
  • Binding Sites
  • Carboxylic Acids / chemistry
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Chelating Agents / chemistry*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism
  • Humans
  • Models, Molecular*
  • Phenylenediamines / chemistry
  • Protein Conformation
  • Structure-Activity Relationship
  • Zinc / chemistry*

Substances

  • Benzamides
  • Carboxylic Acids
  • Chelating Agents
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Phenylenediamines
  • 1,2-diaminobenzene
  • Histone Deacetylases
  • Zinc