Optimization of gefitinib analogues with potent anticancer activity

Bioorg Med Chem Lett. 2014 Nov 15;24(22):5247-50. doi: 10.1016/j.bmcl.2014.09.056. Epub 2014 Sep 28.

Abstract

The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues.

Keywords: A549; Anti-cancer; EGFR; Gefitinib; Iressa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Gefitinib
  • Humans
  • Piperazines / chemistry
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology*

Substances

  • Antineoplastic Agents
  • Piperazines
  • Quinazolines
  • ErbB Receptors
  • Gefitinib