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Semi-synthesis, topoisomerase I and kinases inhibitory properties, and antiproliferative activities of new rebeccamycin derivatives

2003; Elsevier BV; Volume: 11; Issue: 23 Linguagem: Inglês

10.1016/j.bmc.2003.09.014

1464-3391

Pascale Moreau, Nathalie Gaillard, Christelle Marminon, Fabrice Anizon, Nathalie Dias, Brigitte Baldeyrou, Christian Bailly, Alain St. Pierre, John A. Hickman, Bruno Pfeiffer, Pierre Renard, Michelle Prudhomme,

Synthesis and Biological Activity

In the course of structure-activity relationship studies, new rebeccamycin derivatives substituted in 3,9-positions on the indolocarbazole framework, and a 2',3'-anhydro derivative were prepared by semi-synthesis from rebeccamycin. The antiproliferative activities against nine tumor cell lines were determined and the effect on the cell cycle of murine leukemia L1210 cells was examined. Their DNA binding properties and inhibitory properties toward topoisomerase I and three kinases PKCzeta, CDK1/cyclin B, CDK5/p25 and a phosphatase cdc25A were evaluated. The 3,9-dihydroxy derivative is the most efficient compound of this series toward CDK1/cyclin B and CDK5/p25. It is also characterized as a DNA binding topoisomerase I poison. Its broad spectrum of molecular activities likely accounts for its cytotoxic potential. This compound which displays a tumor cell line-selectivity may represent a new lead for subsequent drug design in this series of glycosylated indolocarbazoles.