title: Semi-synthesis, topoisomerase I and kinases inhibitory properties, and antiproliferative activities of new rebeccamycin derivatives.
abstract: 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.
authors: Université Blaise Pascal, Synthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504, 63177, Aubière, France.
authors: Pascale
authors: P
authors: Moreau
authors: Nathalie
authors: N
authors: Gaillard
authors: Christelle
authors: C
authors: Marminon
authors: Fabrice
authors: F
authors: Anizon
authors: Nathalie
authors: N
authors: Dias
authors: Brigitte
authors: B
authors: Baldeyrou
authors: Christian
authors: C
authors: Bailly
authors: Alain
authors: A
authors: Pierré
authors: John
authors: J
authors: Hickman
authors: Bruno
authors: B
authors: Pfeiffer
authors: Pierre
authors: P
authors: Renard
authors: Michelle
authors: M
authors: Prudhomme
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; C053339:rebeccamycin; D010770:Phosphotransferases