School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem. 2018 Jul 30;26(13):3812-3824. doi: 10.1016/j.bmc.2018.06.018. Epub 2018 Jun 14.
To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC = 1.7 and 2.7 μM, respectively), Aβ disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ aggregation, with inhibitory rate 82.7% and 85.7% at 25 μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by HO, okadaic acid (OA) and Aβ without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.
为了开发针对阿尔茨海默病（AD）的有效多靶标配体，设计、合成并评价了一系列新型双价β-咔啉衍生物。体外研究表明，这些化合物表现出良好的多功能活性。特别是化合物 8f 和 8g 对 BuChE 抑制表现出良好的选择性效力（IC=1.7 和 2.7 μM），Aβ 解聚和神经保护作用。与阳性对照白藜芦醇相比，化合物 8f 和 8g 在抑制 Aβ 聚集方面表现出更好的活性，在 25 μM 时抑制率分别为 82.7%和 85.7%。此外，化合物 8e、8f 和 8g 通过改善 HO、冈田酸（OA）和 Aβ 诱导的损伤，在 SH-SY5Y 细胞中没有细胞毒性，表现出优异的神经保护活性。因此，本研究显然表明，化合物 8f 和 8g 是针对 AD 的有效多功能药物，可能成为进一步开发的有前途的候选药物。
