Modular synthesis and biological activity of pyridyl-based analogs of the potent Class I Histone Deacetylase Inhibitor Largazole

Bioorg Med Chem. 2015 Aug 1;23(15):5061-5074. doi: 10.1016/j.bmc.2015.03.063. Epub 2015 Mar 31.

Abstract

The formation of a series of analogs containing a pyridine moiety in place of the natural thiazole heterocycle, based on the potent, naturally occurring HDAC inhibitor Largazole has been accomplished. The synthetic strategy was designed modularly to access multiple inhibitors with different aryl functionalities containing both the natural depsipeptide and peptide isostere variant of the macrocycle. The cytotoxicity and biochemical activity of the library of HDAC inhibitors is described herein.

Keywords: Class I Histone Deacetylase Inhibitor; Cytotoxic and biochemical assays; Largazole; Pyridine analogs.

Publication types

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

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Depsipeptides / chemical synthesis
  • Depsipeptides / chemistry*
  • Depsipeptides / toxicity
  • Drug Design
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / toxicity
  • Histone Deacetylases / chemistry*
  • Histone Deacetylases / metabolism
  • Humans
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Pyridines / chemistry
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / toxicity

Substances

  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Pyridines
  • Thiazoles
  • largazole
  • Histone Deacetylases
  • pyridine