Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S)-3,14,18,19-Tetrahydroangustines as Novel Topoisomerase I Inhibitors
Strictosidine Synthase Triggered Enantioselective Synthesis of N-Substituted (S)-3,14,18,19-Tetrahydroangustines as Novel Topoisomerase I Inhibitors
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马球糖苷合酶触发对映选择性合成 N-取代的 (S)-3,14,18,19-四氢安古斯汀作为新型拓扑异构酶 I 抑制剂
DOI：
10.1021/acschembio.7b00740
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发表时间：
2017-12-01
影响因子：
4
通讯作者：
Zou, Hongbin
中科院分区：
文献类型：
--
作者：
Cai, Yunrui;Zhu, Huajian;Zou, Hongbin
单萜类吲哚生物碱（MIAs）是一类重要的药物发现分子，它们具有不同的碳骨架，具有突出的生物活性。例如，尽管使用受到限制，喜树碱是唯一临床批准的拓扑异构酶I （Topl）抑制剂。应用MIA生物合成的关键酶- strictosidine合成酶对映选择性制备了3个n -取代(S)-3,14,18,19-四氢古斯汀（THA）衍生物。这些非喜树碱类mia具有中等的HepG2体外细胞毒性和Topl抑制活性。与化学合成的(R)对映体相比，(S)构型的MIAs具有更强的细胞毒性和Topl抑制作用，这与分子动力学模拟结果一致。然后用化学酶法合成了一系列n -取代(S)-THAs，以研究其结构与活性关系。观察到的最活跃的类似物是N-（2-氯苯甲酰）取代衍生物（7i）。通过分子动力学模拟研究了7i和一个Topl DNA共价复合物的结合模式，这将有助于未来优化非喜树碱MIAs的Topl抑制活性。
Monoterpenoid indole alkaloids (MIAs) comprise an important class of molecules for drug discovery, and they have variant carbon skeletons with prominent bioactivities. For instance, in spite of limitations to their use, camptothecins are the only clinically approved topoisomerase I (Topl) inhibitors. The enzyme strictosidine synthase, which is key for MIA biosynthesis, was applied to the enantioselective preparation of three N-substituted (S)-3,14,18,19-tetrahydroangustine (THA) derivatives. These non-camptothecin MIAs were shown to have moderate in vitro HepG2 cytotoxicity and Topl inhibition activities. The (S)-configured MIAs had stronger cytotoxicity and Topl inhibition than their chemically synthesized (R)-enantiomers, which aligned with the results of molecular dynamics simulations. A series of N-substituted (S)-THAs were then chemoenzymatically synthesized to investigate structure activity relationships. The most active analogue observed was the N-(2-Cl benzoyl)-substituted derivative (7i). Insight into the binding mode of 7i and a Topl DNA covalent complex was investigated by molecular dynamics simulations, which will facilitate future efforts to optimize the Topl inhibitory activities of non-camptothecin MIAs.