Design and synthesis of 4,6-substituted-(diaphenylamino)quinazolines as potent EGFR inhibitors with antitumor activity

Bioorg Med Chem. 2012 Jan 1;20(1):317-23. doi: 10.1016/j.bmc.2011.10.085. Epub 2011 Nov 6.

Abstract

A type of novel 4,6-substituted-(diaphenylamino)quinazolines, which designed based on the 4-(phenylamino)quinazoline moiety, have been discovered as potential EGFR inhibitors. These compounds displayed good antiproliferative activity and EGFR-TK inhibitory activity. Especially, 4-((4-(3-bromophenylamino)quinazolin-6-ylamino)methyl)phenol (5b), showed the most potent inhibitory activity (IC(50)=0.28μM for Hep G2, IC(50)=0.59μM for A16-F10 and IC(50)=0.87μM for EGFR) and effectively induces apoptosis in a dose-dependent manner in the Hep G2 cell line. Molecular docking of 5b into EGFR TK active site was also performed. This inhibitor nicely fitting the active site might well explain its excellent inhibitory activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Design*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Hep G2 Cells
  • Humans
  • Molecular Conformation
  • Phenols / chemical synthesis*
  • Phenols / chemistry
  • Phenols / pharmacology
  • Protein Structure, Tertiary
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology

Substances

  • 4-((4-(3-bromophenylamino)quinazolin-6-ylamino)methyl)phenol
  • Antineoplastic Agents
  • Phenols
  • Quinazolines
  • ErbB Receptors