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

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• 作者：Chenlu Zhang ; Xiaoyin Wang ; Jin Cui ; Xiaohang Li ; Yangming Zhang ; Xin Wang ; Haifeng Gu ; Wei Li ; Xin Xie ; Jian Zhao ; Gang Pei and Fajun Nan
• 刊名：Chinese Journal of Chemistry
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：35
• 期：1
• 页码：103-112
• 全文大小：688K
• ISSN：1614-7065

文摘

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-α-Akebonoic acid, which emanated from a high throughput screening (HTS), was discovered to interfere with PS1/BACE1 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 PS1/BACE1 interaction inhibitor, which reduced Aβ generation effectively.