Antitumor agents .173. Synthesis and evaluation of camptothecin-4 beta-amino-4'-O-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents
Antitumor agents .173. Synthesis and evaluation of camptothecin-4 beta-amino-4'-O-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents
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DOI：
10.1016/s0968-0896(97)00102-8
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发表时间：
1997-08-01
影响因子：
3.5
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Bastow, KF;Wang, HK;Lee, KH
合成了喜树碱和4‘-O-去甲表鬼臼毒素亚胺键连接的两种偶联物，并评价了它们对哺乳动物DNA拓扑异构酶I和II的抑制作用。目标化合物在体外能刺激这两种酶形成可切割的复合体，但活性比未结合组分的活性至少降低一倍。最具活性的结合物作为细胞生长抑制物的行为与拓扑异构酶I和II抑制组分非常相似，因为该化合物显示出对各种耐药KB亚系的联合活性光谱。细胞毒活性和选择性在很大程度上是通过结合来保持的，除了对多营养多药耐药亚系的活性低于预期。细胞蛋白相关DNA复合体的诱导水平和性质与拓扑异构酶的参与和体外切割试验结果一致。根据目前的发现，结合提供了可切割的形成复杂的拓扑异构酶抑制剂，显示出双重靶点特异性和广泛的细胞毒活性对耐药细胞。(C)1997年，爱思唯尔科学有限公司出版。
Two conjugates composed of a camptothecin and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as inhibitors of mammalian DNA topoisomerases I and II. Target compounds stimulated cleavable complex formation with both types of enzyme in vitro although activities were reduced at least twofold relative to the activity of unconjugated constituents. The behavior of the most active conjugate as an inhibitor of cell growth closely resembled both topoisomerase I- and II- inhibitory components in that the compound displayed a combined spectrum of activity against various drug-resistant KB sublines. Cytotoxic activity and selectivity were largely retained through conjugation, the exception being a lower than expected activity against a pleiotrophic multidrug-resistant subline. The induced levels and the properties of cellular protein-associated DNA complexes were consistent with topoisomerase involvement and with the in vitro cleavage assay results. Based on the present findings, conjugation afforded cleavable complex-forming topoisomerase inhibitors which display dual target specificity and a broad spectrum of cytotoxic activity against drug-resistant cells. (C) 1997 Published by Elsevier Science Ltd.