Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of indolylpyrazolones and indolylpyridazinedioneReport as inadecuate




Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of indolylpyrazolones and indolylpyridazinedione - Download this document for free, or read online. Document in PDF available to download.

* Corresponding author 1 SEESIB - Synthèse et étude de systèmes à intêret biologique 2 SEESIB SEESIB - Synthèse et étude de systèmes à intêret biologique

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 IC50 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

Keywords : Indolylpyrazolones Indolyl-pyridazin-3 6-dione Antitumor agents Chk1 inhibitors





Author: Elisabeth Conchon - Fabrice Anizon - Roy Golsteyn Stéphane Léonce Bruno Pfeiffer Michelle Prudhomme -

Source: https://hal.archives-ouvertes.fr/



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