Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Bioorg Med Chem. 2018 Jul 23;26(12):3191-3201. doi: 10.1016/j.bmc.2018.04.043. Epub 2018 Apr 22.
A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced Aβ aggregation and potential antioxidant properties especially compound 5b (IC = 5.64 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu/Zn-induced Aβ aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin HO and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood-brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000 mg/kg in vivo. Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy.
一系列多靶点 8-羟基喹啉衍生物被设计并合成用于治疗阿尔茨海默病（AD）。体外研究表明，大多数所制备的化合物对自诱导 Aβ聚集具有显著的抑制作用，且具有潜在的抗氧化特性，特别是化合物 5b（对自诱导 Aβ聚集的半数抑制浓度（IC50）为 5.64μM；使用荧光素（ORAC-FL）的氧自由基吸收能力值为 2.63 个 Trolox 当量）。值得注意的是，5b 可以螯合生物金属并抑制 Cu/Zn 诱导的 Aβ聚集。细胞试验表明，5b 对氧化毒素 HO 具有优异的保护作用，且在 PC12 细胞中表现出较低的神经毒性。此外，5b 可以在体外穿透血脑屏障（BBB），并且在体内剂量高达 2000mg/kg 时，在小鼠中没有显示出任何急性毒性。我们的研究结果为化合物 5b 作为 AD 治疗的先导化合物的潜在应用提供了依据。
