Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors
Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors
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作为拓扑异构酶 I 抑制剂的新型 4-(4-取代酰胺基苄基)呋喃-2(5H)-酮衍生物
DOI：
10.1016/j.ejmech.2016.12.035
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发表时间：
2017-02-15
影响因子：
6.7
通讯作者：
Chen, Wei -Min
中科院分区：
文献类型：
--
作者：
Peng, Cheng-Kang;Zeng, Ting;Chen, Wei -Min
在这项研究中，两个系列的新的4-（4-取代氨基苄基）呋喃-2（5 H）-酮衍生物含有一个α，β-不饱和内酯片段的合成和筛选Topo I抑制和抗肿瘤活性。评价了拓扑异构酶I抑制活性和对三种人癌细胞株（MCF-7、Hela、A549）的细胞毒作用。结果表明，系列2，在呋喃酮环上带有环外双键的化合物，通常显示出比系列1，缺少环外双键的化合物更有效的活性。系列2的几种化合物具有显著的Topo I抑制活性和针对癌细胞系的有效抗增殖活性。对系列2（B-15）中活性最强的化合物的进一步作用机理研究表明，合成的化合物不仅能稳定药物-酶-DNA共价三元复合物和喜树碱，而且能干扰Topo I与DNA的结合。这些化合物与拓扑异构体I的结合模式和构效关系进行了讨论。(C)2016 Elsevier Masson SAS。All rights reserved.
In this study, two series of novel 4-(4-substitute damidobenzyl)furan-2(5H)-one derivatives containing an alpha,(beta-unsaturated lactone fragment were synthesized and screened for Topo I inhibition and antitumor activity. The topoisomerase I inhibitory activities and cytotoxicities against three human cancer cell lines (MCF-7,Hela,A549) were evaluated. The results revealed that series 2, compounds bearing an exocyclic double bond on the furanone ring, generally showed more potent activity than series 1, compounds lacking an exocyclic double bond. Several compounds of series 2 possess significant Topo I inhibitory activity and potent antiproliferative activity against cancer cell lines. Further mechanism studies of the most active compound of series 2 (B-15) indicated that synthetic compounds can not only stabilize the drug-enzyme-DNA covalent ternary complex as well as camptothecin, but also interfere with the binding between Topo I and DNA. The binding patterns of these compounds with Topo I and structure-activity relationships are discussed. (C) 2016 Elsevier Masson SAS. All rights reserved.