Structure-based discovery of cytotoxic dimeric tetrahydroxanthones as potential topoisomerase I inhibitors from a marine-derived fungus
Structure-based discovery of cytotoxic dimeric tetrahydroxanthones as potential topoisomerase I inhibitors from a marine-derived fungus
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基于结构的细胞毒性二聚四氢氧杂蒽酮作为海洋源性真菌潜在拓扑异构酶 I 抑制剂的发现
DOI：
10.1016/j.ejmech.2018.02.041
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发表时间：
2018-03-25
影响因子：
6.7
通讯作者：
Li, Dehai
中科院分区：
文献类型：
--
作者：
Wu, Guangwei;Qi, Xin;Li, Dehai
DNA拓扑异构酶I （Topo I）是一种重要的抗癌药物靶点，而山酮二聚体被认为是一种新的Topo I抑制剂化学型。根据二聚体口山酮的结构特征，从红树源真菌vericolor Aspergillus中分离到5个新的二聚体口山酮（1-5）和2个已知的SAD异构体（6和7）。化合物1-7的绝对构型，包括中心和轴向手性元素，是通过ECD比较，化学转化和生物遗传学考虑相结合建立的。化合物1 ~ 7具有较高的结构多样性，并表现出不同程度的细胞毒性。所选的新化合物1、2和5显示出Topo I抑制特性，其中最有效的化合物1，即化合物2的缩二聚体，被证实可以通过靶向Topo I抑制Topo I介导的DNA松弛，从而阻止细胞周期过程并诱导癌细胞坏死。分子对接研究表明，化合物1可以通过pi-pi相互作用与DNA结合，通过氢键与DNA Topo I结合形成三元配合物。(C) 2018 Elsevier Masson SAS。版权所有。
DNA topoisomerase I (Topo I) is an important anticancer drug target, and xanthone dimers are considered to be a new kind of Topo I inhibitor chemotypes. Based on the characteristics of dimeric xanthone structures, five new dimeric xanthones (1-5) and two known SAD isomers (6 and 7) were isolated from the mangrove-derived fungus Aspergillus vericolor. The absolute configurations of compounds 1-7, entailing both central and axial chirality elements, were established by a combination of ECD comparison, chemical conversions, and biogenetic considerations. Compounds 1-7 possessed high structural diversity and exhibited cytotoxicity at different levels. The selected new compounds 1, 2, and 5 showed Topo I inhibition properties and the most potent compound 1, an atropisomer of compound 2, was confirmed to inhibit Topo I-mediated DNA relaxation by targeting Topo I, thereby, arresting the cell cycle process and inducing necrosis in cancer cells. Molecular docking studies showed that compound 1 could bind DNA by pi-pi interaction and DNA Topo I by hydrogen bonds to form a ternary complex. (C) 2018 Elsevier Masson SAS. All rights reserved.