Synthesis and anti-tyrosine kinase activity of 3-(substituted-benzylidene)-1, 3-dihydro-indolin derivatives: investigation of their role against p60c-Src receptor tyrosine kinase with the application of receptor docking studies

Farmaco. 2005 Jun-Jul;60(6-7):497-506. doi: 10.1016/j.farmac.2005.01.015.

Abstract

A series of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-thione derivatives were synthesized as modified congeners of 3-(substituted-benzylidene)-1, 3-dihydro-indolin-2-one series. All the synthesized compounds were examined for their in vitro anti-tyrosine kinase activity against p60c-Src. The activity results revealed that compounds (Z)-3-(4'-Dimethylamino-benzylidene)-1, 3-dihydro-indolin-2-thione (12) (E)-3-(2', 6'-Dichloro-benzylidene)-1, 3-dihydro-indolin-2-thione (13) and (E)-3-(3'-Hydroxy-4'-methoxy-benzylidene)-1, 3-dihydro-indolin-2-thione (19) exhibited anti-tyrosine kinase activity with IC50 value of 21.91, 21.20 and 30.92 microM, respectively. These results are comparable to PP1 [1-tert-Butyl-3-p-tolyl-1H-pyrazolo[3, 4-d]pyrimidine-4-yl-amine] (IC50=0.17 microM), which is reported as a potent and selective p60c-Src tyrosine kinase inhibitor. Some thio congeners are found to be more potent than oxo derivatives; however, no significant correlation was observed between the activity profiles of these two series. Docking program was used to investigate the docking mode of each compound at the active site. Among all of the compounds, only (Z)-3-(2'-Chloro-benzylidene)-1, 3-dihydro-indolin-2-one (8) and (E)-3-(3'-Nitro-benzylidene)-1, 3-dihydro-indolin-2-thione (16) were docked at the active site where the PP1 was embedded.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Benzylidene Compounds / chemistry*
  • Binding, Competitive
  • Indoles / chemical synthesis
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism

Substances

  • Benzylidene Compounds
  • Indoles
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins pp60(c-src)
  • src-Family Kinases