Asymmetric synthesis of tetrahydroquinoline-type ecdysone agonists and QSAR for their binding affinity against Aedes albopictus ecdysone receptors
Asymmetric synthesis of tetrahydroquinoline-type ecdysone agonists and QSAR for their binding affinity against Aedes albopictus ecdysone receptors
复制标题
四氢喹啉型蜕皮激素激动剂的不对称合成及其与白纹伊蚊蜕皮激素受体结合亲和力的 QSAR
DOI：
10.1002/ps.5160
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发表时间：
2019
影响因子：
4.1
通讯作者：
Hisashi Miyagawa
中科院分区：
文献类型：
--
作者：
Taiyo Yokoi;Yoshiaki Nakagawa;Hisashi Miyagawa
背景四氢喹啉（THQ）是一类非甾体蜕皮激素激动剂，特异性结合蚊子蜕皮激素受体（EcR）。 THQ 支架在 C-2 和 C-4 位置包含两个手性中心，产生四种立体异构体。我们之前已经表明，(2R,4S)-异构体最具生物活性；然而，这些异构体缺乏实用的合成方法，阻碍了进一步的结构-活性研究。 结果在本研究中，采用手性磷酸催化的波瓦洛夫反应来开发具有(2R,4S)构型的THQ的简便不对称合成，从而可以制备对映体纯THQ的40种化合物库。评估它们对白纹伊蚊 EcR 的结合亲和力，然后进行定量结构-活性关系 (QSAR) 分析，揭示了 THQ 的理化特性，这些特性对于配体-受体相互作用很重要。最有效的 THQ 衍生物的活性是蜕皮激素 20-羟基蜕皮激素的两倍。结论 QSAR 结果为合理设计新型蚊子特异性蜕皮激素激动剂提供了有价值的信息。 © 2018 中国化学工业学会
BACKGROUNDTetrahydroquinolines (THQs) are a class of non‐steroidal ecdysone agonists that specifically bind to mosquito ecdysone receptors (EcR). The THQ scaffold contains two chiral centers at the C‐2 and C‐4 positions, resulting in four stereoisomers. We have previously shown that the (2R,4S)‐isomers are the most biologically active; however, the lack of a practical synthetic method for these isomers has hampered further structure–activity studies.RESULTSIn this study, a chiral phosphoric acid‐catalyzed Povarov reaction was employed to develop a facile asymmetric synthesis of THQs with a (2R,4S)‐configuration, which allowed the preparation of a 40‐compound library of enantiopure THQs. Evaluation of their binding affinity againstAedes albopictusEcR, followed by quantitative structure–activity relationship (QSAR) analyses, uncovered the physicochemical properties of THQs that are important for the ligand–receptor interaction. The most potent THQ derivative was twofold more active than the molting hormone, 20‐hydroxyecdysone.CONCLUSIONThe QSAR results provide valuable information for the rational design of novel mosquito‐specific ecdysone agonists. © 2018 Society of Chemical Industry