Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of indolylpyrazolones and indolylpyridazinedione

Eur J Med Chem. 2006 Dec;41(12):1470-7. doi: 10.1016/j.ejmech.2006.06.012. Epub 2006 Sep 22.

Abstract

The synthesis of 5-indolylpyrazol-3-one, 4-indolylpyrazol-3-one and 4-indolyl-pyridazin-3,6-dione is reported. Their Chk1 inhibitory properties have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, human colon carcinoma HT29 and HCT116 have been determined. 4-Indolyl-pyridazin-3,6-dione is inactive against Chk1 and exhibits weak cytotoxicities toward the tumor cell lines tested. The IC(50) values toward Chk1 of the two indolylpyrazolones are identical and are in the micromolar range, but the cytotoxicities of 4-indolylpyrazol-3-one are significantly stronger than those of 5-indolylpyrazol-3-one. Since 4-indolylpyrazol-3-one and 5-indolylpyrazol-3-one can present several conformers and tautomeric forms, molecular modelling in the ATP binding site of Chk1 has been carried out to investigate which form could induce the best stabilization in the active site of the enzyme. To get an insight into the kinase selectivity of these compounds, their inhibitory activities toward Src kinase were evaluated.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Checkpoint Kinase 1
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mice
  • Models, Molecular
  • Protein Kinases / drug effects*
  • Pyrazolones / chemical synthesis*
  • Pyrazolones / pharmacology*
  • Pyridazines / chemical synthesis*
  • Pyridazines / pharmacology*
  • Spectrophotometry, Infrared

Substances

  • Pyrazolones
  • Pyridazines
  • Protein Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse