Synthesis and activity of novel 5-substituted pyrrolo[2,3-d]pyrimidine analogues as pp60(c-Src) tyrosine kinase inhibitors

Arch Pharm (Weinheim). 2008 Feb;341(2):113-20. doi: 10.1002/ardp.200700141.

Abstract

Therapy with receptor tyrosine kinase inhibitors provides an improved treatment option in a number of diseases such as cancer, myocardial infection, osteoporosis, stroke, and neurodegeneration. We have designed, synthesized, and evaluated a series of novel 2-amino-5-[(benzyl)imino]methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one 7a and 2-amino-5-[(substituted-benzyl)imino]methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidine-4-one 7b-e derivatives as potential tyrosine kinase inhibitors. These compounds were synthesized by condensation reaction using 2-tritylamino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde 5 and appropriate benzylamines followed by detritylation. Compounds were evaluated for their inhibitory activity toward tyrosine phosphorylation for the pp60c-Src tyrosine kinase. Compounds 7a, 7d, and 7e demonstrated potent inhibitory activities against pp60c-Src tyrosine kinase with IC50 values of 13.9, 34.5, and 78.4 microM, respectively. Dihalogenated compounds 7d and 7e have 3 to 7-times lower IC50 values than that of the parent compound 7a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors*
  • Proto-Oncogene Proteins pp60(c-src) / chemistry
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Structure-Activity Relationship

Substances

  • Pyrimidines
  • Pyrroles
  • Proto-Oncogene Proteins pp60(c-src)