Structural optimization and biological evaluation of substituted bisphenol A derivatives as beta-amyloid peptide aggregation inhibitors.
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.
Zhou
Yu
Y
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Jiang
Chunyi
C
Zhang
Yaping
Y
Liang
Zhongjie
Z
Liu
Wenfeng
W
Wang
Liefeng
L
Luo
Cheng
C
Zhong
Tingting
T
Sun
Yi
Y
Zhao
Linxiang
L
Xie
Xin
X
Jiang
Hualiang
H
Zhou
Naiming
N
Liu
Dongxiang
D
Liu
Hong
H
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
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)