Synthesis and biological evaluation of novel naphthocarbazoles as potential anticancer agents.

Animals; Antineoplastic Agents/chemical synthesis/chemistry/pharmacology; Carbazoles/chemical synthesis/chemistry/pharmacology; Cell Cycle/drug effects; Cell Line, Tumor; Cell Proliferation/drug effects; Cyclin-Dependent Kinases/antagonists & inhibitors; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Mice; Naphthalenes/chemical synthesis/chemistry/pharmacology; Phthalimides/chemical synthesis/chemistry/pharmacology; Structure-Activity Relationship; Topoisomerase I Inhibitors

Abstract :

[en] 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.

Disciplines :

Chemistry

Author, co-author :

Routier, Sylvain

Peixoto, Paul

Merour, Jean-Yves

Coudert, Gerard

Dias, Nathalie

Bailly, Christian

Pierre, Alain

Leonce, Stephane

Caignard, Daniel-Henry

Language :

English

Title :

Synthesis and biological evaluation of novel naphthocarbazoles as potential anticancer agents.

Publication date :

2005

Journal title :

Journal of Medicinal Chemistry

ISSN :

0022-2623

eISSN :

1520-4804

Publisher :

American Chemical Society, Washington, United States - District of Columbia

Volume :

Issue :

Pages :

1401-13

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 03 March 2011

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