School of Life Science and Technology, Weifang Medical University, Shandong, China.
Institute of Basic and Transitional Medicine, Xi'an Medical University, Shannxi, China.
Bioorg Chem. 2023 Apr;133:106378. doi: 10.1016/j.bioorg.2023.106378. Epub 2023 Jan 18.
A series of new α-carboline analogues modified at N or N positions by alkyl, benzyl and phenyl were synthesized and characterized as potential ligands for AD therapy. These compounds exhibited multifunctional neurobiological activities including anti-neuroinflammatory, neuroprotective and cholinesterase inhibition. Among them, compound 5d with good drug-like properties and no cytotoxicity, showed potent inhibitory activity against NO production (IC = 1.45 μM), which could suppress the expression levels of iNOS and COX-2 in a dose-dependent manner. Further mechanism exploration indicated that compound 5d could regulate the NF-κB signaling pathway by decreasing the phosphorylation of IκB-α and p65. Notably, compound 5d could effectively decrease the LPS-induced aberrations in zebrafish. Compounds 3b, 4f, 5c, 5g, 5m and 6i exhibited potential neuroprotective activity (cell viability > 70 %) in the HO-induced PC-12 neuronal death model and rescued the SOD activity. In particular, compounds 3b, 4f, and 5g activated the Nrf2 signaling pathway, and improved the expressions of antioxidant proteins NQO-1 and HO-1, which alleviated the head cell apoptosis in zebrafish. Additionally, compound 6i exhibited potential inhibitory activity against BuChE with IC of 0.77 μM. Overall, this work provided some lead compounds based on α-carboline used for AD therapy.
一系列在 N 或 N 位被烷基、苄基和苯基修饰的新型 α-咔啉类似物被合成并作为 AD 治疗的潜在配体进行了表征。这些化合物表现出多种神经生物学活性，包括抗炎、神经保护和乙酰胆碱酯酶抑制作用。其中，化合物 5d 具有良好的类药性和无细胞毒性，对 NO 产生具有很强的抑制活性（IC = 1.45 μM），可以剂量依赖性地抑制 iNOS 和 COX-2 的表达水平。进一步的机制研究表明，化合物 5d 可以通过降低 IκB-α 和 p65 的磷酸化来调节 NF-κB 信号通路。值得注意的是，化合物 5d 可以有效减少 LPS 诱导的斑马鱼中的异常。化合物 3b、4f、5c、5g、5m 和 6i 在 HO 诱导的 PC-12 神经元死亡模型中表现出潜在的神经保护活性（细胞活力>70%），并挽救了 SOD 活性。特别是，化合物 3b、4f 和 5g 激活了 Nrf2 信号通路，提高了抗氧化蛋白 NQO-1 和 HO-1 的表达，减轻了斑马鱼中的头部细胞凋亡。此外，化合物 6i 对 BuChE 表现出潜在的抑制活性，IC 为 0.77 μM。总的来说，这项工作提供了一些基于 α-咔啉的用于 AD 治疗的先导化合物。
