Synthesis and biochemical evaluation of a series of aminoflavones as potential inhibitors of protein-tyrosine kinases p56lck, EGFr, and p60v-src

J Med Chem. 1994 Sep 30;37(20):3353-62. doi: 10.1021/jm00046a020.

Abstract

A series of nitroflavones, 8a-p, and their corresponding aminoflavone hydrochloride salts, 10a-p, was synthesized. The preparation of nitroflavones 8b-i,o,p began with commercially available o-hydroxyacetophenones 2b-f which were converted to o-hydroxynitroacetophenones 3a-h via a variety of nitration methods, followed by condensation with nitrobenzoyl chlorides and cyclization under acidic condition. The nitroflavones 8aj-n were prepared by nitration of the corresponding flavones 7a-e. These new compounds were evaluated for their abilities to inhibit the in vitro protein-tyrosine kinase activities of p56lck, EGFr, and p60v-src, and all of the active compounds were amino-substituted flavones. None of the nitroflavones inhibited the enzymes. The most active substance in this series against p56lck was compound 10j, which had an IC50 of 18 microM. When tested versus EGFr, compounds 10a,m displayed IC50's of 8.7 and 7.8 microM, respectively. Against p60v-src, 10a,m showed IC50 values of 28.8 and 38.4 microM, respectively.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Binding Sites
  • ErbB Receptors / antagonists & inhibitors*
  • Flavonoids / chemical synthesis*
  • Flavonoids / pharmacology
  • Humans
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Methylation
  • Molecular Structure
  • Oncogene Protein pp60(v-src) / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Flavonoids
  • 6-hydroxy-4',5,7-triaminoflavone
  • Adenosine Triphosphate
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Oncogene Protein pp60(v-src)