DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA.
DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA.
复制标题
DOI：
--
复制
发表时间：
1989-11
期刊：
影响因子：
11.2
通讯作者：
A. Bodley;Leroy F. Liu;M. Israel;R. Seshadri;Y. Koseki;F. Giuliani;S. Kirschenbaum;R. Silber
中科院分区：
文献类型：
--
作者：
A. Bodley;Leroy F. Liu;M. Israel;R. Seshadri;Y. Koseki;F. Giuliani;S. Kirschenbaum;R. Silber
本研究中使用了三组多柔比星和柔红霉素类似物，不同之处在于它们在发色团和糖部分上的取代基。测试3 '-N-未取代的（组1）、3'-N-酰基（组2）和3 '-N-烷基（组3）类似物的：（a）体内抗肿瘤活性和体外细胞毒性;（B）细胞或组织摄取和代谢转化;（c）DNA嵌入的强度;和（d）与DNA拓扑异构酶II（topo-II）的相互作用。第1组的化合物是细胞毒性的，是强烈的嵌入，除了那些与C-14侧链取代，诱导形成拓扑-II-DNA可切割复合物。如前所示，需要C-14-酰基取代基的酯水解以产生可与纯化系统中的拓扑-II相互作用的代谢物。第2组的C-14-取代化合物及其C-14-未取代代谢物具有细胞毒性。这些药物是弱嵌入剂，并且C-14-未取代的同源物在纯化的系统中诱导可裂解的复合物形成，但相对于多柔比星具有降低的效力。3 '-N-位取代基的类型决定了第3组类似物是否具有细胞毒性和强嵌入剂，或者活性较低和非嵌入性。虽然C-14-未取代的嵌入剂组3没有形成可裂解的复合物在纯化的系统中，它们是细胞毒性的。该研究表明，DNA嵌入是必需的，但不足以通过topo-II靶向的蒽环类药物的活性。除了参与嵌入的平面发色团之外，蒽环类分子的另外两个结构域对于与topo-II的相互作用是重要的：（a）C-14位的取代完全抑制了纯化系统中的药物活性，但通过帮助药物摄取和可能作用于其它细胞靶点而增强了细胞毒性;和（B）根据取代基的性质，糖环3 '-N位置上的取代可以抑制嵌入和/或topo-II靶向活性。这些发现可能为合成和开发新的活性类似物提供指导。
Three groups of doxorubicin and daunorubicin analogues, differing by their substituents on the chromophore and sugar moieties, were used in this study. The 3'-N-unsubstituted (Group 1), 3'-N-acyl (Group 2), and 3'-N-alkyl (Group 3) analogues were tested for: (a) in vivo antitumor activity and in vitro cytotoxicity; (b) cellular or tissue uptake and metabolic conversion; (c) strength of DNA intercalation; and (d) interaction with DNA topoisomerase II (topo-II). Compounds of Group 1 were cytotoxic, were strongly intercalative, and, except for those with C-14 side chain substitution, induced the formation of topo-II-DNA cleavable complexes. As shown previously, esterolysis of C-14-acyl substituents was required to yield a metabolite which can interact with topo-II in the purified system. The C-14-substituted compounds of Group 2 and their C-14-unsubstituted metabolites were cytotoxic. These drugs were weak intercalators, and the C-14-unsubstituted cogeners induced cleavable complex formation in the purified system, but with reduced potency relative to doxorubicin. The type of the 3'-N-position substituent determined whether Group 3 analogues were cytotoxic and strong intercalators, or less active and nonintercalating. Although C-14-unsubstituted intercalators of Group 3 did not form cleavable complexes in the purified system, they were cytotoxic. The study shows that DNA intercalation is required but not sufficient for the activity by topo-II-targeted anthracyclines. In addition to the planar chromophore which is involved in intercalation, two other domains of the anthracycline molecule are important for the interaction with topo-II: (a) substitution of the C-14 position totally inhibits drug activity in the purified system, but enhances cytotoxicity by aiding drug uptake and presumably acting on other cellular targets; and (b) substitutions on the 3'-N position of the sugar ring can, depending on the nature of the substituent, inhibit intercalation and/or topo-II-targeting activity. These findings may provide guidance for the synthesis and development of new active analogues.