Evaluation of class I HDAC isoform selectivity of largazole analogues

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3728-31. doi: 10.1016/j.bmcl.2014.07.006. Epub 2014 Jul 9.

Abstract

Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure-activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors.

Keywords: Class I histone deacetylase; HDAC inhibitor; Isoform selectivity; Largazole; Structure–activity relationship.

Publication types

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

MeSH terms

  • Depsipeptides / chemical synthesis
  • Depsipeptides / chemistry
  • Depsipeptides / pharmacology*
  • Dose-Response Relationship, Drug
  • Histone Deacetylase 1 / antagonists & inhibitors*
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Isoenzymes
  • Thiazoles
  • largazole
  • HDAC1 protein, human
  • Histone Deacetylase 1