Design, synthesis and antiproliferative activities of novel benzamides derivatives as HDAC inhibitors

Eur J Med Chem. 2015 Jul 15:100:270-6. doi: 10.1016/j.ejmech.2015.05.045. Epub 2015 Jun 5.

Abstract

Guided by the principle of nonclassical electronic isosterism and structural optimization, a series of novel HDAC inhibitors bearing a bicyclic heterocycle moiety were designed and synthesized based on the lead compound of MS-275. All the prepared compounds were evaluated for their in vitro antiproliferative activities against HCT-116, MCF-7 and A549 human cancer cell lines, all compounds exerted excellent antitumor activities. Moreover, the compound 4a exhibited an acceptable pharmacokinetic profile with bio-availability in rat of 76% and could be considered as a candidate compound for further development.

Keywords: Acrylamide; Antiproliferative; Benzamides derivatives; HDAC; Pharmacokinetic; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Biological Availability
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • HCT116 Cells
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • MCF-7 Cells
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases