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Synthetic Analogues of Betulinic Acid as Potent Inhibitors of PS1/BACE1 Interaction to Reduce Aβ Generation

ISSN号：1001-604X
期刊名称：《中国化学：英文版》
分类：S941.41[农业科学—水产养殖;农业科学—水产科学] TD923.14[矿业工程—选矿]
作者机构：[1]National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, [2]State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, [3]Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongii University, Shanghai 200092, China
相关基金：This research was supported by the National Natural Science Foundation of China （Nos. 81573267, 91413103 and 91213303）.

作者： Chenlu Zhang[1], Xiaoyin Wang[1], Jin Cui[2], Xiaohang Li[2], Yangming Zhang[1], Xin Wang[2], Haifeng Gu[1], Wei Li[2], Xin Xie[1], Jian Zhao[2], Gang Pei[2,3], Fajun Nan[1]

关键词：相互作用, 抑制剂, PS1, 合成类似物, 三萜类化合物, 脂酸, 白桦, 阿尔茨海默病, Alzheimer＇s disease, PS 1/BACE 1 interaction, Aβ, betulinic acid, SAR

中文摘要：

lupane 类型 triterpenoids 被赋予以大量生物活动例如抗病毒，反煽动性并且 anticancer 活动。我们这里在 Alzheimers 描述它的潜在的申请疾病(广告) 治疗作为 PS1/BACE1 的一个禁止者相互作用。3-α-Akebonoic 酸，从高产量发出了屏蔽，被发现防碍 PS1/BACE1 相互作用和还原剂淀粉的 β-protein (Aβ) 生产。鉴于有限来源，当为铅优化和它的衍生物的一个集中的图书馆的开始的材料被构造获得 PS1/BACE1 相互作用的 triterpenoid 类型禁止者的结构活动关系(SAR ) 的更好的理解，我们相反使用了自然地富有的 betulinic 酸(化合物 2 ) 。化合物 22 最后被选择为大多数有势力 PS1/BACE1 相互作用禁止者，它有效地减少了 Aβ 产生。

英文摘要：

The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer＇s disease （AD） treatment as an inhibitor of PS1/BACE1 interaction. 3-a-Akebonoic acid, which emanated from a high throughput screening （HTS）, was discovered to interfere with P S 1/BACE 1 interaction and reduce amyloid β-protein （Aβ） production. In view of the limited source, we instead used naturally rich betulinic acid （compound 2） as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship （SAR） of triterpenoid-type inhibitor of PS1/BACE1 interaction. Compound 22 was finally chosen as the most potent PS 1/BACE 1 interaction inhibitor, which reduced Aβgeneration effectively.