Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC

Eur J Med Chem. 2016 Feb 15:109:1-12. doi: 10.1016/j.ejmech.2015.12.033. Epub 2015 Dec 20.

Abstract

A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast cancer cell line MCF-7 with IC50 of 0.85 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for cancer therapy deserving further researching.

Keywords: Dual inhibitor; HDAC; N-Phenylquinazolin-4-amine hybrid; VEGFR-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amination
  • Cell Proliferation / drug effects
  • Drug Design
  • Female
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Humans
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Histone Deacetylase Inhibitors
  • Quinazolines
  • Vascular Endothelial Growth Factor Receptor-2
  • Histone Deacetylases