Calories from carbohydrates: energetic contribution of the carbohydrate moiety of rebeccamycin to DNA binding and the effect of its orientation on topoisomerase I inhibition

被引:44
作者
Bailly, C [1 ]
Qu, XG
Graves, DE
Prudhomme, M
Chaires, JB
机构
[1] Ctr Oscar Lambret, F-59045 Lille, France
[2] INSERM, U524, F-59045 Lille, France
[3] Univ Mississippi, Med Ctr, Dept Biochem, Jackson, MS 39216 USA
[4] Univ Blaise Pascal, CNRS, UMR 6504, F-63177 Aubiere, France
[5] Univ Mississippi, Dept Chem, University, MS 38677 USA
来源
CHEMISTRY & BIOLOGY | 1999年 / 6卷 / 05期
关键词
carbohydrate-DNA recognition; indolocarbazole; rebeccamycin; stereospecificity; topoisomerase I;
D O I
10.1016/S1074-5521(99)80073-8
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
Background: Only a few antitumor drugs inhibit the DNA breakage-reunion reaction catalyzed by topoisomerase. One is the camptothecin derivative topotecan that has recently been used clinically. Others are the glycosylated antibiotic rebeccamycin and its synthetic analog NB-506, which is presently in phase I of clinical trials. Unlike the camptothecins, rebeccamycin-type compounds bind to DNA. We set out to elucidate the molecular basis of their interaction with duplex DNA, with particular emphasis on the role of the carbohydrate residue. Results: We compared the DNA-binding and topoisomerase-I-inhibition activities of two isomers of rebeccamycin that contain a galactose residue attached to the indolocarbazole chromophore via an alpha (axial) or a beta (equatorial) glycosidic linkage. The modification of the stereochemistry of the chromophore-sugar linkage results in a marked change of the DNA-binding and topoisomerase I poisoning activities. The inverted configuration at the C-1' of the carbohydrate residue abolishes intercalative binding of the drug to DNA thereby drastically reducing the binding affinity. Consequently, the alpha isomer has lost the capacity to induce topoisomerase-I-mediated cleavage of DNA. Comparison with the aglycone allowed us to determine the energetic contribution of the sugar residue. Conclusions: The optimal interaction of rebeccamycin analogs with DNA is controlled to a large extent by the stereochemistry of the sugar residue. The results clarify the role of carbohydrates in stereospecific drug-DNA interactions and provide valuable information for the rational design of new rebeccamycin-type antitumor agents.
引用
收藏
页码:277 / 286
页数:10
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