title: Multitarget-directed oxoisoaporphine derivatives: Anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced autophagy activity against Alzheimer's disease.
abstract: 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.
authors.affiliation: State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China.
authors.forename: Shenqi
authors.initials: S
authors.lastname: Wei
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin 541004, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China.
authors.forename: Jingfang
authors.initials: J
authors.lastname: Qin
authors.affiliation: Affiliated Hospital of Guilin Medicine University, Guilin 541004, China.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Huangli
authors.affiliation: State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China. Electronic address: hyhth@163.com.
authors.forename: Huang
authors.initials: H
authors.lastname: Tang
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001060:Aporphines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D001060:Aporphines; D002800:Cholinesterase Inhibitors; D066329:Protein Aggregates; D000110:Acetylcholinesterase
keywords: Autophagy; Cholinesterase inhibitors; Oxoisoaporphine derivatives; Synthesis; β-Amyloid aggregation