ANTITUMOR AGENTS .113. NEW 4BETA-ARYLAMINO DERIVATIVES OF 4'-O-DEMETHYLEPIPODOPHYLLOTOXIN AND RELATED-COMPOUNDS AS POTENT INHIBITORS OF HUMAN DNA TOPOISOMERASE-II
ANTITUMOR AGENTS .113. NEW 4BETA-ARYLAMINO DERIVATIVES OF 4'-O-DEMETHYLEPIPODOPHYLLOTOXIN AND RELATED-COMPOUNDS AS POTENT INHIBITORS OF HUMAN DNA TOPOISOMERASE-II
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DOI：
10.1021/jm00171a050
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发表时间：
1990-09-01
影响因子：
7.3
通讯作者：
LEE, KH
中科院分区：
文献类型：
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作者：
WANG, ZQ;KUO, YH;LEE, KH
已经合成了许多具有各种4.β-N、4.β-O-或4.β-S-芳香环的4''-O-去甲基表鬼臼毒素衍生物，并评估了它们对人DNA拓扑异构酶II的抑制活性以及它们引起细胞蛋白连接的DNA断裂的活性。结果表明，对于DNA拓扑异构酶II，增强的活性在结构上需要碱性未取代的4.β.-苯胺基部分。该部分在对位和/或间位被 CN、COOCH3、COOCH2H5、OH 和 COOCH3、OCH3、COCH3、CH2OH、OCH2O、OCH2CH2O、苯氧基、吗啉代、NO2 和 NH2 取代，产生与依托泊苷一样有效或更有效的化合物。在邻位用 COOC2H5 和 OH 取代得到无活性的化合物。用氧或硫取代芳基氮得到活性低得多或无活性的化合物。然而，用吡啶核取代苯环提供了与依托泊苷活性相同或稍强的化合物。这些化合物抑制 DNA 拓扑异构酶 II 的能力与导致蛋白连接的 DNA 断裂的能力之间缺乏相关性。
A number of 4''-O-demethylepipodophyllotoxin derivatives possessing various 4.beta.-N, 4.beta.-O- or 4.beta.-S-aromatic rings have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results indicated, that for DNA toposoimerase II, a basic unsubstituted 4.beta.-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOCH2H5, OH and COOCH3, OCH3, COCH3, CH2OH, OCH2O, OCH2CH2O, phenoxy, morpholino, NO2, and NH2 either at the para and/or the meta position yielded compounds which are as potent or more potent than etoposide. Substitution with COOC2H5 and OH at the ortho position afforded inactive compounds. Replacement of the aryl nitrogen with oxygen or sulfur gave compounds which are much less active or inactive. However, replacement of the phenyl ring with a pyridine nucleus furnished compounds which are as active or slightly more active than etoposide. There is a lack of correlation between the ability of these compounds in inhibiting DNA topoisomerase II and is causing protein-linked DNA breaks.