Potent histone deacetylase inhibitors derived from 4-(aminomethyl)-N-hydroxybenzamide with high selectivity for the HDAC6 isoform

J Med Chem. 2013 Sep 26;56(18):7201-11. doi: 10.1021/jm400385r. Epub 2013 Sep 4.

Abstract

A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.

MeSH terms

  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / pharmacology*
  • Substrate Specificity

Substances

  • Benzamides
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • benzamide
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases