Antitumor agents .177. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors
Antitumor agents .177. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors
复制标题
DOI：
10.1016/s0960-894x(97)00060-7
复制
发表时间：
1997-03-04
影响因子：
2.7
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Ji, Z;Wang, HK;Lee, KH
设计用于增强小沟结合能力的新型水溶性4 β-氨基-4 ′-O-去甲基表鬼臼毒素衍生物（6-12）被合成并针对NCI的体外疾病导向的人肿瘤细胞进行筛选。其中，发现4 '-O-去甲基-4 β-[N-（1-三甲基-4-三甲基-硝基-吡咯-2-三甲基-羰基）-4“-氨基苯胺基]-4-脱氧鬼臼毒素（10）及其盐酸盐（11）显示出有效的细胞毒活性（10、11和依托泊苷的平均log GI（50）分别为-6.91、-7.00和-5.01）。进一步测试化合物10和12对DNA拓扑异构酶II的抑制活性。与依托泊苷相比，化合物10再次显示出上级活性特征，显示出对KB和KB-7 d细胞的细胞毒性增加（KB和KB-7 d细胞的ID 50/LD（50）分别为0.04/0.15和0.2/0.25），拓扑异构酶II抑制活性（12.5 μ M），和细胞蛋白DNA复合物形成（225%）。(C)1997 Elsevier Science Ltd.保留所有权利。
Novel water-soluble 4 beta-amino-4'-O-demethylepipodophyllotoxin derivatives (6-12), designed to enhance minor groove binding ability, were synthesized and screened against NCI's in vitro disease-oriented human tumor cells. Among them, 4'-O-demethyl-4 beta-[N-(1 triple prime-methyl-4 triple prime-nitro-pyrrole-2 triple prime-carbonyl)-4 ''-aminoanilino]-4-desoxypodophyllotoxin (10) and its HCl salt (11) were found to exhibit potent cytotoxic activities (average log GI(50) = -6.91, -7.00, and -5.01 for 10, 11, and etoposide, respectively). Compounds 10 and 12 were further tested for their inhibitory activities against DNA topoisomerase II. Compound 10 again exhibited a superior activity profile compared to that of etoposide, displaying increased cytotoxicity against KB and KB-7d cells (ID50/LD(50) = 0.04/0.15 and 0.2/0.25 for KB and KB-7d cells, respectively), topoisomerase II inhibitory activity (12.5 mu M), and cellular protein DNA complex formation (225%). (C) 1997 Elsevier Science Ltd. All rights reserved.