title: 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.
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.
authors.affiliation: Laboratoire SEESIB, Université Blaise Pascal, UMR 6504 du CNRS, 24, avenue des Landais, 63177 Aubière, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Conchon
authors.forename: Fabrice
authors.initials: F
authors.lastname: Anizon
authors.forename: Bettina
authors.initials: B
authors.lastname: Aboab
authors.forename: Roy M
authors.initials: RM
authors.lastname: Golsteyn
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Michelle
authors.initials: M
authors.lastname: Prudhomme
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000071877:Checkpoint Kinase 1; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared
chemical_list: D002227:Carbazoles; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse