Xu Zi-Chen, Wang Xiao-Bing, Yu Wen-Ying, Xie Sai-Sai, Li Su-Yi, Kong Ling-Yi
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
Bioorg Med Chem Lett. 2014 May 15;24(10):2368-73. doi: 10.1016/j.bmcl.2014.03.058. Epub 2014 Apr 3.
A novel series of benzylisoquinoline derivatives were designed, synthesized, and evaluated as multifunctional agents against Alzheimer's disease (AD). The screening results showed that most of the compounds significantly inhibited cholinesterases (ChEs), human cholinesterases (h-ChEs) and self-induced β-amyloid (Aβ) aggregation. In particular, compound 9k showed the strongest acetylcholinesterase (AChE) inhibitory activity, being 1000-fold and 3-fold more potent than its precursor benzylisoquinoline (10) and the positive control galanthamine, respectively. In addition, 9k was a moderately potent inhibitor for h-ChEs. Compared with precursor benzylisoquinoline (36.0% at 20μМ), 9k (78.4% at 20μМ) could further inhibit Aβ aggregation. Moreover, 9k showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Therefore, compound 9k might be a promising lead compound for AD treatment.
设计、合成了一系列新型苄基异喹啉衍生物，并将其作为抗阿尔茨海默病（AD）的多功能药物进行评估。筛选结果表明，大多数化合物能显著抑制胆碱酯酶（ChEs）、人胆碱酯酶（h-ChEs）以及自身诱导的β-淀粉样蛋白（Aβ）聚集。特别地，化合物9k表现出最强的乙酰胆碱酯酶（AChE）抑制活性，分别比其前体苄基异喹啉（10）和阳性对照加兰他敏强1000倍和3倍。此外，9k是h-ChEs的中度有效抑制剂。与前体苄基异喹啉（20μМ时为36.0%）相比，9k（20μМ时为78.4%）能进一步抑制Aβ聚集。而且，9k在人SH-SY5Y神经母细胞瘤细胞中表现出低细胞毒性。因此，化合物9k可能是一种有前景的AD治疗先导化合物。
