Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl- 7H-pyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents

Aleem Gangjee, Ying Zhao, Sudhir Raghavan, Michael A. Ihnat, Bryan C. Disch

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

A series of 2-amino-4-m-bromoanilino-6-benzyl pyrrolo[2,3-d]pyrimidines analogues 4-12 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). These analogues were synthesized from the appropriate α-bromomethylbenzylketones via cyclocondensation with 2,6-diamino-4- pyrimidone to afford the 2-amino-4-oxo-6-substituted benzyl pyrrolo[2,3-d] pyrimidines. Chlorination at the 4-position followed by displacement with 3-bromoaniline or 3-bromo-N-methylaniline and methylation of the 7-NH afforded the target compounds. Remarkably, dimethylation of both the 4-N and N7 afford whole cell EGFR inhibitors that are more cytotoxic than clinically used erlotinib and mono-methylation at the 4-N or N7 affords more cytotoxic whole cell PDGFR-β inhibitors than clinically used sunitinib. Methylation at either the 4-N or N7 position was detrimental to whole cell VEGFR-2 inhibition. The inhibitory data against the RTKs in this study demonstrates that methylation of the 4-NH and/or the 7-NH influences both the specificity and potency of RTK inhibition.

Original languageEnglish (US)
Pages (from-to)5261-5273
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number14
DOIs
StatePublished - Jul 15 2010

Keywords

  • Antiangiogenic agents
  • Multiple receptor
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

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

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