Novel securinine derivatives as topoisomerase I based antitumor agents
Novel securinine derivatives as topoisomerase I based antitumor agents
复制标题
作为基于拓扑异构酶 I 的抗肿瘤剂的新型叶秋碱衍生物
DOI：
10.1016/j.ejmech.2016.06.021
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发表时间：
2016-10-21
影响因子：
6.7
通讯作者：
Chen, Wei-Min
中科院分区：
文献类型：
--
作者：
Hou, Wen;Wang, Zhen-Ya;Chen, Wei-Min
DNA拓扑异构酶I（Topo I）已被验证为抗癌剂的靶标。本研究设计并合成了一系列具有β ′-羟基-α，β-不饱和酮结构的一叶秋碱衍生物，并通过Baylis-Hillman反应筛选了其作为Topo I抑制剂和抗肿瘤药物的活性。评价了它们的拓扑异构酶I抑制活性以及它们对四种人癌细胞系（A549、HeLa、HepG 2、SH-SY 5 Y）的细胞毒性，并且鉴定了两对非对映体4a-1和4a-6具有显著的拓扑异构酶I抑制活性和有效的抗癌细胞系增殖活性。通过X-射线衍射和圆二色谱分析，确定了5对非对映异构体的绝对构型。对活性最高的化合物4a-1-R和4a-1-S的进一步机制研究表明，这类一叶秋碱衍生物具有与已被证实的Topo I抑制剂喜树碱不同的抑制机制。与喜树碱不同，化合物4a-1-R和4a-1-S特异性抑制Topo I和DNA的结合，而不是形成药物-酶-DNA共价三元复合物。此外，分子对接和分子动力学研究揭示了这些化合物与Topo I的结合模式。(C)2016 Elsevier Masson SAS。All rights reserved.
DNA topoisomerase I (Topo I) has been validated as a target for anticancer agents. In this study, a series of novel securinine derivatives bearing beta'-hydroxy-alpha,beta-unsaturated ketone moiety were designed and synthesized via a Baylis-Hillman reaction for screening as Topo I inhibitors and antitumor agents. Their topoisomerase I inhibitory activity as well as their cytotoxicity against four human cancer cell lines (A549, HeLa, HepG2, SH-SY5Y) were evaluated, and two pairs of diastereomers 4a-1 and 4a-6 with significant Topo I inhibitory activity and potent anti-proliferative activity against cancer cell lines were identified. The diastereomers were separated, and absolute configurations of five pairs of diastereomers were identified based on X-ray crystallographic analysis and circular dichroism (CD) spectra analysis. Further mechanism studies of the most active compounds 4a-1-R and 4a-1-S indicated that this kind of securinine derivative exhibits a different inhibitory mechanism from that of camptothecin, an established Topo I inhibitor. Unlike camptothecin, compounds 4a-1-R and 4a-1-S specifically inhibits the combination of Topo I and DNA rather than forming the drug-enzyme-DNA covalent ternary complex. In addition, molecular docking and molecular dynamic studies revealed the binding patterns of these compounds with Topo I. (C) 2016 Elsevier Masson SAS. All rights reserved.