Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5137-41. doi: 10.1016/j.bmcl.2015.10.006. Epub 2015 Oct 8.

Abstract

A series of hybrids derived from 4-anilinoquinazoline and hydroxamic acid were designed, synthesized, and evaluated as dual inhibitors of vascular endothelia growth factor receptor-2 (VEGFR-2) tyrosine kinase and histone deacetylase (HDAC). Most of these compounds exhibited potent HDAC inhibition and moderate VEGFR-2 inhibition. Among them, compound 6l exhibited the most potent inhibitory activities against VEGFR-2 (IC50=84 nM) and HDAC (IC50=2.8 nM). It also showed the most potent antiproliferative ability against MCF-7, a human breast cancer line, with IC50 of 1.2 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction of compound 6l at the active binding sites of VEGFR-2 and HDAC.

Keywords: 4-Anilinoquinazoline; HDAC; Hybrid; Hydroxamic acid; VEGFR-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Catalytic Domain
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

  • 4-(4-(2,4-dichlorophenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxybutanamide
  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Protein Kinase Inhibitors
  • Quinazolines
  • Vascular Endothelial Growth Factor Receptor-2