Synthesis and biological activity of 5-chloro-N4-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic agents

Aleem Gangjee, Nilesh Zaware, Sudhir Raghavan, Bryan C. Disch, Jessica E. Thorpe, Anja Bastian, Michael A. Ihnat

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Inhibition of receptor tyrosine kinase (RTK) signaling pathways is an important area for the development of novel anticancer agents. Numerous multikinase inhibitors (MKIs) have been recently approved for the treatment of cancer. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the principal mediator of tumor angiogenesis. In an effort to develop ATP-competitive VEGFR-2 selective inhibitors the 5-chloro-N4-substituted phenyl-9H-pyrimido[4,5-b]indole-2,4-diamine scaffold was designed. The synthesis of the target compounds involved N-(4,5-dichloro-9H-pyrimido[4,5-b]indol-2-yl)- 2,2-dimethylpropanamide) as a common intermediate. A nucleophilic displacement of the 4-chloro group of the common intermediate by appropriately substituted anilines afforded the target compounds. Biological evaluation indicated that compound 5 is a potent and selective VEGFR-2 inhibitor comparable to sunitinib and semaxinib.

Original languageEnglish (US)
Pages (from-to)1857-1864
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2013

Keywords

  • Cytotoxicity
  • Pyrimido[4,5-b]indol synthesis
  • Receptor tryosine kinase inhibitors
  • VEGFR-2 inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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