基于多奈哌齐与姜黄素融合的抗阿尔茨海默病多靶点导向配体的设计、合成与评价
Design, synthesis, and evaluation of multitarget-directed ligands against Alzheimer's disease based on the fusion of donepezil and curcumin.
作者信息
Yan Jun, Hu Jinhui, Liu Anqiu, He Lin, Li Xingshu, Wei Hui
机构信息
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China; Guangdong Cosmetics Engineering & Technology Research Center, Zhongshan 528458, China.
出版信息
Bioorg Med Chem. 2017 Jun 15;25(12):2946-2955. doi: 10.1016/j.bmc.2017.02.048. Epub 2017 Apr 18.
By fusing donepezil and curcumin, a novel series of compounds were obtained as multitarget-directed ligands against Alzheimer's disease. Among them, compound 11b displayed potent acetylcholinesterase (AChE) inhibition (IC=187nM) and the highest BuChE/AChE selectivity (66.3). Compound 11b also inhibited 45.3% Aβ self-aggregation at 20μM and displayed remarkable antioxidant effects. The metal-chelating property of compound 11b was elucidated by determining the 1:1 stoichiometry for the 11b-Cu(II) complex. The excellent blood-brain barrier permeability of 11b also indicated the potential for the compound to penetrate the central nervous system.
通过将多奈哌齐和姜黄素融合，获得了一系列新型化合物作为针对阿尔茨海默病的多靶点导向配体。其中，化合物11b表现出强效的乙酰胆碱酯酶（AChE）抑制作用（IC = 187nM）以及最高的丁酰胆碱酯酶/乙酰胆碱酯酶选择性（66.3）。化合物11b在20μM时还能抑制45.3%的Aβ自我聚集，并表现出显著的抗氧化作用。通过确定11b - 铜（II）配合物的1:1化学计量比，阐明了化合物11b的金属螯合特性。11b优异的血脑屏障通透性也表明该化合物具有穿透中枢神经系统的潜力。
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