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

被引:22
作者
Moreau, P
Gaillard, N
Marminon, C
Anizon, F
Dias, N
Baldeyrou, B
Bailly, C
Pierré, A
Hickman, J
Pfeiffer, B
Renard, P
Prudhomme, M [1 ]
机构
[1] Univ Clermont Ferrand, UMR 6504, F-63177 Clermont Ferrand, France
[2] IRCL, INSERM U524, F-59045 Lille, France
[3] IRCL, Lab Pharmacol Antitumorale, Ctr Oscar Lambret, F-59045 Lille, France
[4] Inst Rech Servier, Div Rech Cancerol, F-78290 Croissy Sur Seine, France
[5] Les Lab SERVIER, F-92415 Courbevoie, France
关键词
D O I
10.1016/j.bmc.2003.09.014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, CDKI/cyclin B, CDK5/p25 and a phosphatase cdc25A were evaluated. The 3,9-dihydroxy derivative is the most efficient compound of this series toward CDKI/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. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:4871 / 4879
页数:9
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