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

Bioorg Med Chem. 2010 Jul 15;18(14):5261-73. doi: 10.1016/j.bmc.2010.05.049. Epub 2010 May 25.

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 alpha-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-beta 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry*
  • Angiogenesis Inhibitors / pharmacology*
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism
  • Humans
  • Models, Molecular
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor beta / chemistry
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Protein Kinase Inhibitors
  • Pyrimidines
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor beta
  • Vascular Endothelial Growth Factor Receptor-2