The semi-synthesis of novel andrographolide analogues and anti-influenza virus activity evaluation of their derivatives
The semi-synthesis of novel andrographolide analogues and anti-influenza virus activity evaluation of their derivatives
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新型穿心莲内酯类似物的半合成及其衍生物的抗流感病毒活性评价
DOI：
10.1016/j.bmcl.2015.12.100
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发表时间：
2016-02-01
影响因子：
2.7
通讯作者：
Chen, Lixia
中科院分区：
文献类型：
--
作者：
Yuan, Lei;Zhang, Chunfeng;Chen, Lixia
首次合成了以Delta(8，17)-烯烃异构化为结构基元的两个新的穿心莲内酯类似物AI78和AI89。根据合成路线设计合成了两个系列的衍生物(包括系列I：烯烃异构化为内环Delta(8，9)和系列II：烯烃异构化为内环Delta(7，8))。对所有化合物的体外抗流感病毒活性进行了评价。在所合成的化合物中，含苄氨基的化合物38的抗H3N_2活性最强，约为中国临床用穿心莲内酯类似物连必治的1.5倍。43岁的金刚烷基衍生物毒性最低，其TC50和TI值高于连必治。合成的类似物的构效关系研究表明，内环Delta(7，8)-双键具有较好的抗病毒作用。此外，在C-17的刚性骨架上引入脂肪氨基有利于活性。(C)2016爱思唯尔有限公司。保留所有权利。
Two novel andrographolide analogues with the structural motif of Delta(8,17)-alkene exo-to-endo isomerization, AI78 and AI89, were semi-synthesized firstly. Two series of derivatives were designed and synthesized based on the synthetic pathway (including series I: olefin isomerizing to endocyclic Delta(8,9) and series II: olefin isomerizing to endocyclic Delta(7,8)). The anti-influenza virus activity in vitro for all derivatives was evaluated. Among the compounds synthesized, compound 38 with benzyl amino group showed the greatest potency against H3N2 and was approximately 1.5-fold more potent than that of Lianbizhi, andrographolide analogue used clinically in China. Adamantyl derivative, 43, presented the lowest toxicity, with a higher TC50 and TI values than Lianbizhi. The structure-activity relationships studies of the synthetic analogues indicated that the endocyclic Delta(7,8)-double bond is preferable for anti-viral effect. Furthermore, the introduction of the fatty amino attached to the rigid skeleton at C-17 is beneficial for activity. (C) 2016 Elsevier Ltd. All rights reserved.