title: Synthesis and biological evaluation of novel naphthocarbazoles as potential anticancer agents.
abstract: We report the efficient synthesis involving palladium-catalyzed reactions and biological evaluation of new naphthocarbazoles designed as potential anticancer agents. The use of 5- and 6-benzyloxyindoles generated three substitution sites which were successively exploited to introduce several hydrophilic side chains. The cytotoxicity of the newly designed compounds was evaluated on three cell lines. Several compounds showed a marked cytotoxicity with IC(50) values in the sub-micromolar range. This is the case for the 3-hydroxy-naphthopyrrolocarbazoledione 37, bearing a dimethylaminoethyl side chain, which is extremely cytotoxic to L1210 and DU145 cells (IC(50): 36 nM, 108 nM) and induces an accumulation of L1210 cells in the G2+M phases of the cell cycle. Some of the most cytotoxic compounds were tested for inhibition of CDK-5, GSK-3 and topoisomerase I, and their interaction with DNA was also evaluated. Interaction with DNA was detected, suggesting that nucleic acids represent a privileged target for these molecules.
authors.affiliation: Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d'orléans, Rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France. sylvain.routier@univ.orleans.fr
authors.forename: Sylvain
authors.initials: S
authors.lastname: Routier
authors.forename: Paul
authors.initials: P
authors.lastname: Peixoto
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Mérour
authors.forename: Gérard
authors.initials: G
authors.lastname: Coudert
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dias
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Daniel-Henry
authors.initials: DH
authors.lastname: Caignard
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: C499139:3-hydroxy-6-(2-(dimethylamino)ethyl)naphtho(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6H,14H)-dione; D000970:Antineoplastic Agents; D002227:Carbazoles; D009281:Naphthalenes; D010797:Phthalimides; D059004:Topoisomerase I Inhibitors; D018844:Cyclin-Dependent Kinases