Synthesis and biological evaluation of novel naphthocarbazoles as potential anticancer agents.
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.
Routier
Sylvain
S
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
Peixoto
Paul
P
Mérour
Jean-Yves
JY
Coudert
Gérard
G
Dias
Nathalie
N
Bailly
Christian
C
Pierré
Alain
A
Léonce
Stéphane
S
Caignard
Daniel-Henry
DH
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
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