Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation |
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Authors: | Peng Lv Chun-Li Xia Ning Wang Zhen-Quan Liu Zhi-Shu Huang Shi-Liang Huang |
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Affiliation: | 1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China;2. Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, People’s Republic of China |
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Abstract: | Amyloid-β (Aβ) and tau protein are two crucial hallmarks in Alzheimer’s disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aβ and tau aggregation. In vitro studies showed that compounds 25–30 (20?μM) with N-methylation of the quinolone ring effectively inhibited Aβ1-42 aggregation by 84.7%–99.5% and tau aggregation by 71.2%–101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to Aβ1-42 and tau, inhibit Aβ1-42 β-sheets formation, and prevent tau aggregation in living cells. |
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Keywords: | AD Alzheimer’s disease Aβ amyloid-β BBB blood-brain barrier CAs cinnamic acid derivatives CD circular dichroism DAPI 4′,6-diamidino-2-phenylindole DMED Dulbecco’s modified Eagle’s medium DMSO dimethylsulfoxide HRMS high resolution mass spectra LMTM leucomethylene blue NFT intracellular neurofibrillary tangles PBL porcine brain lipid SPR surface plasmon resonance TEM transmission electron microscope ThS Thioflavin S ThT Thioflavin T Alzheimer’s disease Amyloid β Tau protein Aggregation inhibitors 1,2,3,4-Tetrahydro-1-acridone analogues |
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