Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
Cells. 2020 Mar 7;9(3):649. doi: 10.3390/cells9030649.
Due to the complicated pathogenesis of Alzheimer's disease (AD), the development of multitargeted agents to simultaneously interfere with multiple pathological processes of AD is a potential choice. Glycogen synthase kinase-3β (GSK-3β) plays a vital role in the AD pathological process. In this study, we discovered a novel 1-pyrrolo[2,3-b]pyridine derivative B10 as a GSK-3β inhibitor that features with a quinolin-8-ol moiety to target the metal dyshomeostasis of AD. B10 potently inhibited GSK-3β with an IC of 66 ± 2.5 nM. At the concentration of 20 μM, B10 increased β-catenin abundance (β-catenin/GAPDH: 0.83 ± 0.086 vs. 0.30 ± 0.016), phosphorylated GSK-3β at Ser9 (p-GSK-3β/GAPDH: 0.53 ± 0.045 vs. 0.35 ± 0.012), and decreased the phosphorylated tau level (p-tau/GAPDH: 0.33 ± 0.065 vs. 0.83 ± 0.061) in SH-SY5Y cells. Unlike other GSK-3β inhibitors, B10 had a direct effect on Aβ by inhibiting Aβ aggregation and promoting the Aβ aggregate disassociation. It selectively chelated with Cu, Zn, Fe and Al, and targeted AD metal dyshomeostasis. Moreover, B10 effectively increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth, possibly through the GSK-3β and β-catenin signal pathways. Therefore, B10 is a potent and unique GSK-3β inhibitor that has a direct on Aβ and serves as a multifunctional anti-AD agent for further investigations.
由于阿尔茨海默病（AD）的发病机制复杂，开发同时干扰 AD 多种病理过程的多靶点药物是一种潜在的选择。糖原合酶激酶-3β（GSK-3β）在 AD 病理过程中起着至关重要的作用。在本研究中，我们发现了一种新型 1-吡咯并[2,3-b]吡啶衍生物 B10，它是一种 GSK-3β 抑制剂，具有喹啉-8-醇部分，可针对 AD 的金属失衡。B10 强烈抑制 GSK-3β，IC 为 66±2.5 nM。在 20μM 浓度下，B10 增加 β-连环蛋白的丰度（β-连环蛋白/GAPDH：0.83±0.086 对 0.30±0.016），磷酸化 GSK-3β 在 Ser9 上（p-GSK-3β/GAPDH：0.53±0.045 对 0.35±0.012），并降低磷酸化 tau 水平（p-tau/GAPDH：0.33±0.065 对 0.83±0.061）在 SH-SY5Y 细胞中。与其他 GSK-3β 抑制剂不同，B10 通过抑制 Aβ 聚集和促进 Aβ 聚集解离，对 Aβ 有直接作用。它选择性螯合 Cu、Zn、Fe 和 Al，靶向 AD 金属失衡。此外，B10 有效增加了公认的神经发生标志物 GAP43、N-myc 和 MAP-2 的 mRNA 表达，并促进了分化神经元的神经突生长，这可能是通过 GSK-3β 和 β-连环蛋白信号通路。因此，B10 是一种有效的、独特的 GSK-3β 抑制剂，对 Aβ 具有直接作用，是一种具有多种功能的抗 AD 药物，值得进一步研究。
