Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone |
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Authors: | Conchon Elisabeth Anizon Fabrice Aboab Bettina Golsteyn Roy M Léonce Stéphane Pfeiffer Bruno Prudhomme Michelle |
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Affiliation: | Laboratoire SEESIB, Université Blaise Pascal, UMR 6504 du CNRS, 24, avenue des Landais, 63177 Aubière, France. |
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Abstract: | The synthesis of substituted pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone is reported. Their inhibitory properties toward Checkpoint 1 kinase (Chk1) 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. From the biological results, it appears that, in contrast with the upper E heterocycle, the lower D heterocycle is not absolutely required for Chk1 inhibition. The ATP binding pocket of Chk1 seems to be adaptable to substitution of the nitrogen of the imide E heterocycle with a hydroxymethyl group, allowing the fundamental hydrogen bond with the Glu(85) residue of the enzyme. |
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