Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors.
Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors.
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DOI：
10.3390/md16090293
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发表时间：
2018-08-21
期刊：
影响因子：
5.4
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Cheng ZQ;Song JL;Zhu K;Zhang J;Jiang CS;Zhang H
合成了海洋天然产物大黄素B(1)和一系列相关的他克林杂化类似物，并对其作为胆碱酯酶(ChE)抑制剂进行了评价。体外胆碱酯酶检测结果表明，1具有中等的乙酰胆碱酯酶(AChE)/丁酰胆碱酯酶(BChE)双重抑制活性，而杂化的12j被证明是所设计的衍生物中最有效的双重抑制剂，其活性几乎与他克林相同。分子模拟研究和动力学分析表明，12j既与AChE的催化活性中心相互作用，又与AChE的外围阴离子中心相互作用。化合物1和12j也能抑制自身诱导和AChE诱导的Aβ聚集。此外，对人肝癌细胞株(HepG2)的细胞实验表明，与他克林和多奈哌齐相比，1和12j没有明显的肝毒性。综上所述，本研究证实了化合物1是一种潜在的抗阿尔茨海默病(AD)药物，12j可能是一种用于抗AD药物开发的多功能先导化合物。
A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aβ aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer’s disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.
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影响因子：
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作者：
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