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 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2008

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

Résumé

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 Glu85 residue of the enzyme
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hal-00255899 , version 1 (14-02-2008)

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  • HAL Id : hal-00255899 , version 1

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Elisabeth Conchon, Fabrice Anizon, Bettina Aboab, Roy Golsteyn, Stéphane Leonce, et al.. 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. European Journal of Medicinal Chemistry, 2008, 43, pp.282-292. ⟨hal-00255899⟩
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