title: Structural optimization and biological evaluation of substituted bisphenol A derivatives as beta-amyloid peptide aggregation inhibitors.
abstract: The aggregation of Abeta is a crucial step in the etiology of Alzheimer's disease. Our previous work showed that Abeta undergoes alpha-helix/beta-sheet intermediate structures during the conformational transition, and an Abeta aggregation inhibitor (1) was discovered by targeting the intermediates. Here, structure optimization toward compound 1 was performed and 34 novel derivatives were designed and synthesized. Nine compounds showed more effective inhibitory activity than the hit compound 1 in ThT fluorescence assay. Among them, compound 43 demonstrated more excellent inhibitory potency, which not only can suppress the aggregation of Abeta but also can dissolve the preformed fibrils as shown by CD spectroscopy, PICUP and AFM assays. Cellular assay indicated that 43 has no toxicity to neuronal cells, moreover, can effectively inhibit Abeta(1-42)-induced neutrotoxicity and increase the cell viability. Together, on the basis of these positive results, these novel chemical structures may provide a promising potential for therapeutic applications in AD and other types of neurodegenerative disorders.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Chunyi
authors.initials: C
authors.lastname: Jiang
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Liu
authors.forename: Liefeng
authors.initials: L
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhong
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Linxiang
authors.initials: L
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Naiming
authors.initials: N
authors.lastname: Zhou
authors.forename: Dongxiang
authors.initials: D
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C551936:3,3'-(4,4'-(propane-2,2-diyl)bis(2,6-dibromo-4,1-phenylene))bis(oxy)bis(1-(3,5-dimethylpiperidin-1-yl)propan-2-ol); D000682:Amyloid; D016229:Amyloid beta-Peptides; D001559:Benzhydryl Compounds; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42)