Arcamone F, Animati F, Bigioni M, Capranico G, Caserini C, Cipollone A, De Cesare M, Ettorre A, Guano F, Manzini S, Monteagudo E, Pratesi G, Salvatore C, Supino R, Zunino F
Menarini Ricerche Sud, Pomezia, Rome, Italy.
Biochem Pharmacol. 1999 May 15;57(10):1133-9. doi: 10.1016/s0006-2952(99)00025-8.
The amino sugar is recognized to be a critical determinant of the activity of anthracycline monosaccharides related to doxorubicin and daunorubicin. In an attempt to improve the pharmacological properties of such agents, novel anthracycline disaccharides have been designed in which the amino sugar, daunosamine, is separated from the aglycone by another carbohydrate moiety. In the present study, we examined the influence of the orientation of the second sugar residue on drug biochemical and biological properties in a series of closely related analogs. This structure-activity relationship study showed that the substitution of the daunosamine for the disaccharide moiety dramatically reduced the cytotoxic potency of the drug in the 4-methoxy series (daunorubicin analogs). In contrast, in the 4-demethoxy series (idarubicin analogs), the C-4 axial, but not the equatorial, configuration conferred a cytotoxic potency and antitumor activity comparable to that of doxorubicin. The configuration also influenced the drug's ability to stimulate topoisomerase II alpha-mediated DNA cleavage. Indeed, the glycosides with the equatorial orientation were ineffective as topoisomerase II poisons, whereas the compounds with axial orientation were active, although the daunorubicin analog exhibited a lower activity than the idarubicin analog. It is conceivable that the axial orientation allows an optimal interaction of the drug with the DNA-enzyme complex only in the absence of the methoxy group. Our results are consistent with a critical role of the sugar moiety in drug interaction with the target enzyme in the ternary complex.
氨基糖被认为是与多柔比星和柔红霉素相关的蒽环类单糖活性的关键决定因素。为了改善此类药物的药理学性质，人们设计了新型蒽环类二糖，其中氨基糖柔红糖胺通过另一个碳水化合物部分与糖苷配基分离。在本研究中，我们在一系列密切相关的类似物中研究了第二个糖残基的取向对药物生化和生物学性质的影响。这种构效关系研究表明，在4-甲氧基系列（柔红霉素类似物）中，用二糖部分取代柔红糖胺会显著降低药物的细胞毒性效力。相反，在4-去甲氧基系列（伊达比星类似物）中，C-4轴向而非赤道构型赋予了与多柔比星相当的细胞毒性效力和抗肿瘤活性。这种构型也影响了药物刺激拓扑异构酶IIα介导的DNA切割的能力。实际上，具有赤道取向的糖苷作为拓扑异构酶II毒药无效，而具有轴向取向的化合物具有活性，尽管柔红霉素类似物的活性低于伊达比星类似物。可以想象，只有在没有甲氧基的情况下，轴向取向才允许药物与DNA-酶复合物进行最佳相互作用。我们的结果与糖部分在三元复合物中药物与靶酶相互作用中的关键作用一致。
