Novel 3 ',6 '-anhydro and N12,N13-bridged glycosylated fluoroindolo[2,3-a]carbazoles as topoisomerase I inhibitors. Fluorine as a leaving group from sp(3) carbon
ABSTRACT [reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
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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 IC(50) 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.Journal of Medicinal Chemistry 02/2006; 49(2):789-99. DOI:10.1021/jm050945x · 5.48 Impact Factor
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ABSTRACT: Palladium-catalysed reactions of aryl iodides/vinyl triflates with 2,2,2-trifluoro-N-(2-(4-[2,2,2-trifluoro-acetylamino)-phenyl]buta-1,3-diynyl)-phenyl)-acetamide provide a straightforward entry into 3,3'-disubstituted-2,2'-biindolyls. Subsequent application of the procedure to homochiral aryl iodides affords the corresponding chiral 3,3'-disubstituted-2,2'-biindolyls. The methodology can also be applied to the synthesis of benzo[c]indolo[2,3-a]carbazoles. (c) 2006 Elsevier Ltd. All rights reserved.Tetrahedron 07/2006; 62(13-13):3033-3039. DOI:10.1016/j.tet.2006.01.041 · 2.82 Impact Factor
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ABSTRACT: We describe here an efficient synthesis of new 5-azaindolocarbazoles designed for cytotoxic and Chk1 inhibiting properties. The synthesis of 'symmetrical' and 'dissymmetrical' structures is discussed. Concerning the dissymmetrical 5-azaindolocarbazoles derivatives, with both an indole moiety and a 5-azaindole moiety, the synthesis was achieved using two very efficient key steps. The first one is a Stille reaction with a 3-trimethylstannyl-5-azaindole derivative and the second one a photochemical step leading to the proposed polycyclic structure. Various pharmacomodulations were performed to investigate the structure-activity relationships (SAR). Several substituents such as OBn, OH, and methylenedioxy groups were successfully introduced on the indole moiety of the 5-azaindolocarbazole. Compounds with or without substituents on the nitrogen atom of the maleimide were prepared, as well as derivatives with glucopyranosyl substituent on the nitrogen atom of the indole moiety. The cytotoxicity of these new compounds was evaluated on two cell lines (L1210, HT29). Several compounds showed cytotoxicity in the sub-micromolar range. Among the most cytototoxic was the 1,3-dioxolo[4,5-b]-6-(2-dimethylaminoethyl)-1H-pyrido[3',4':4,5]pyrrolo[3,2-i]pyrrolo[3,4-g]carbazole-5,7(6H,12H)-dione (35, IC(50)=195 nM on L1210). The compounds were also investigated for their Chk1 inhibiting activity. Compounds without any substitution on the maleimide moiety were the most potent. This is the case of compounds 45-47 with IC(50) of, respectively, 72, 27, and 14nM toward Chk1. Compound 46, which exhibits moderate cytotoxicity, appears to be a good candidate for development in a multi-drug anticancer therapy.Bioorganic & medicinal chemistry 06/2008; 16(9):5303-21. DOI:10.1016/j.bmc.2008.02.086 · 2.95 Impact Factor