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

作者：Wei, Shenqi; Chen, Wei; Qin, Jingfang; Huangli, Yingzi; Wang, Li; Shen, Yue; Tang, Huang^*

来源：Bioorganic & Medicinal Chemistry, 2016, 24(22): 6031-6039.

DOI：10.1016/j.bmc.2016.09.061

• Oxoisoaporphine derivatives
• Synthesis
• Cholinesterase inhibitors
• beta-Amyloid aggregation
• Autophagy

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 beta-amyloid (A beta) 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 All aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human beta-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of A beta 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.

• 出版日期2016-11-15
• 单位广西师范大学; 桂林医学院