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Article

Synthesis and Biological Evaluation of Novel Phenylcarbazoles as Potential Anticancer Agents

Supporting Info

Sylvain Routier,*^† Jean-Yves Mérour,^† Nathalie Dias,^‡ Amélie Lansiaux,^‡ Christian Bailly,^‡ Olivier Lozach,^§ and Laurent Meijer^§

Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universit d'Orlans, Rue de Chartres, BP 6759, 45067 Orlans Cedex 2, France; INSERM U-524, IRCL, Place de Verdun, 59045 Lille, France; and Station Biologique, place G. Teissier, B.P. 74, 29682 ROSCOFF Cedex, France

J. Med. Chem., 2006, 49 (2), pp 789–799

DOI: 10.1021/jm050945x

Publication Date (Web): December 23, 2005

Corresponding author. Tel: +33 228 41 49 53. Fax: +33 238 41 72 81. E-mail: sylvain.routier@univ-orleans.fr.

†

Université d'Orléans.

‡

INSERM U-524.

Present address: Centre de Recherche en Oncologie Expérimentale, Institut de Recherche Pierre Fabre, 3 rue des satellites, 31140 Toulouse, France.

Station Biologique.

Abstract

We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC₅₀ values in the 10−100 nM range. Precise structure−activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.

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