Discovery and Biological Evaluations of Halogenated 2,4-Diphenyl Indeno[1,2- b]pyridinol Derivatives as Potent Topoisomerase IIα-Targeted Chemotherapeutic Agents for Breast Cancer

J Med Chem. 2019 Sep 12;62(17):8194-8234. doi: 10.1021/acs.jmedchem.9b00970. Epub 2019 Aug 22.

Abstract

With the aim of developing new effective topoisomerase IIα-targeted anticancer agents, we synthesized a series of hydroxy- and halogenated 2,4-diphenyl indeno[1,2-b]pyridinols using a microwave-assisted single step synthetic method and investigated structure-activity relationships. The majority of compounds with chlorophenyl group at 2-position and phenol group at the 4-position of indeno[1,2-b]pyridinols exhibited potent antiproliferative activity and topoisomerase IIα-selective inhibition. Of the 172 compounds tested, 89 showed highly potent and selective topoisomerase IIα inhibition and antiproliferative activity in the nanomolar range against human T47D breast (2.6 nM) cancer cell lines. In addition, mechanistic studies revealed compound 89 is a nonintercalative topoisomerase II poison, and in vitro studies showed it had promising cytotoxic effects in diverse breast cancer cell lines and was particularly effective at inducing apoptosis in T47D cells. Furthermore, in vivo administration of compound 89 had significant antitumor effects in orthotopic mouse model of breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Biphenyl Compounds / chemical synthesis
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA Topoisomerases, Type II / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Male
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred ICR
  • Microwaves
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Biphenyl Compounds
  • Pyridines
  • Topoisomerase II Inhibitors
  • diphenyl
  • DNA Topoisomerases, Type II