Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced autophagy activity against Alzheimer’s disease

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• 作者：Shenqi Wei^a ; ^&dagger ; ; Wei Chen^b ; ^&dagger ; ; Jingfang Qin^a ; Yingzi Huangli^b ; Li Wang^a ; Yue Shen^a ; Huang Tang^a ; ^{hyhth@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Oxoisoaporphine derivatives ; Synthesis ; Cholinesterase inhibitors ; β-Amyloid aggregation ; Autophagy
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：24
• 期：22
• 页码：6031-6039
• 全文大小：1033 K

文摘

A series of 8- and 11-substituted oxoisoaporphine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase (ChE) in vitro and in vivo, and self-induced β-amyloid (Aβ) aggregation. Their autophagy activity and blood–brain barrier (BBB) permeability were also assessed. The new derivatives exhibited high AChE inhibitory activity in vivo and in intro. Over half the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ secretion levels. Moreover, one-third of the synthetic compounds were predicted to be able to cross the BBB to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Compounds 5b and 6b were chosen for assessing their autophagy activity. The fluorescence intensity of the BC12921 was decreased significantly after treatment with compounds. The result encourages us to study such compounds thoroughly and systematically.