title: Synthesis and biological activities of new checkpoint kinase 1 inhibitors structurally related to granulatimide.
abstract: In the course of structure-activity relationship studies on granulatimide analogues, new pyrrolo[3,4-c]carbazoles in which the imidazole heterocycle has been replaced by a five- or a six-membered ring bearing one or two carbonyl functions have been synthesized. Their checkpoint kinase 1 (Chk1) inhibitory properties and their in vitro antiproliferative activities toward three tumor cell lines-murine leukemia L1210 and human colon carcinoma HT29 and HCT116 have been determined. The results of molecular modeling in the ATP binding pocket of Chk1 are described. Among the newly synthesized compounds, compounds 13 and 16, in which the imidazole was replaced by a quinone and a hydroquinone and which bear a hydroxy group on the indole moiety, are the most potent Chk1 inhibitors in this series with IC50 values of 27 and 23 nM, respectively.
authors.affiliation: Laboratoire SEESIB, Université Blaise Pascal, UMR 6504 du CNRS, 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: Michelle
authors.initials: M
authors.lastname: Prudhomme
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C523628:11-hydroxybenzo(a)pyrrolo(3,4-c)carbazole-1,3,4,7(2H,8H)-tetraone; C523629:4,7,11-trihydroxybenzo(a)pyrrolo(3,4-c)carbazole-1,3(2H,8H)-dione; D000470:Alkaloids; D000970:Antineoplastic Agents; D002227:Carbazoles; D047428:Protein Kinase Inhibitors; C433587:granulatimide; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse