Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4-oxadiazoles derivatives as multifunctional neuroprotective agents
Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4-oxadiazoles derivatives as multifunctional neuroprotective agents
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新型海洋吲哚基1,2,4-恶二唑衍生物作为多功能神经保护剂的合成和生物学评价
DOI：
10.1016/j.bmcl.2014.11.068
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发表时间：
2015-01-15
影响因子：
2.7
通讯作者：
Guo, Yue-Wei
中科院分区：
文献类型：
--
作者：
Jiang, Cheng-Shi;Fu, Yan;Guo, Yue-Wei
Phidianidines（1）是从海洋后鳃类软体动物Phidiana militaris中分离得到的第一个含1，2，4-恶二唑环的天然产物，具有多种生物活性。然而，与1相关的构效关系研究还未见报道。作为我们对海洋来源的潜在神经保护剂的持续影响，已经合成了一系列基于菲迪苯胺的衍生物，并在SH-SY 5 Y细胞中评估了其对淀粉样蛋白-β（25 - 35）（A β（25 -35））-、过氧化氢（H2 O2）-和氧-葡萄糖剥夺（OGD）-诱导的神经毒性的神经保护作用。生物活性测定结果表明，在上述三种筛选模型中，部分类似物，尤其是2 q和2 r，具有较好的体外神经保护作用。初步的构效关系研究表明，苯环上引入的取代基对其生物活性起着至关重要的作用。特别地，在4-位的线性烷氧基有利于神经保护活性，而庞大的基团可能导致活性降低或丧失。这些发现可以为开发用于治疗阿尔茨海默病的新型吲哚基1，2，4-恶二唑衍生物提供替代策略。(C)2014爱思唯尔有限公司版权所有。
Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the first example of natural products possessing an 1,2,4-oxadiazole ring system and show various bioactivities. However, the structure-activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential neuroprotective agents, a series of phidianidine-based derivatives have been synthesized and evaluated for neuroprotective effects against amyloid-beta(25-35) (A beta(25-35))-, hydrogenperoxide (H2O2)-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro neuroprotective effects in the above three screening models. The preliminary SAR study indicated that substituent groups introduced to the benzene ring play a crucial role in their bioactivity. In particular, the linear alkoxy group at 4-position favors the neuroprotective activity, while a bulky group could lead the activity decrease or loss. These findings could provide an alternative strategy for the development of novel indole-based 1,2,4-oxadiazole derivatives for the treatment of Alzheimer's disease. (C) 2014 Elsevier Ltd. All rights reserved.