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有机化学
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有机化学 ›› 2017, Vol. 37 ›› Issue (4): 873-880.DOI: 10.6023/cjoc201611026 上一篇    下一篇

研究论文

栀子酰胺A-他克林杂合体的设计合成及其对6-羟多巴胺诱导的PC12细胞损伤的保护作用

张馨怡a, 袁盛a, 赵家强a, 张磊a, 张潮a, 王日康b, 陈河如a,c   

  1. a. 暨南大学药学院 中药及天然药物研究所 广州 510632;
    b. 江西中医药大学 中药固体制剂制造技术国家工程研究中心 南昌 330006;
    c. 广东省中药药效物质基础及创新药物研究重点实验室 广州 510632
  • 收稿日期:2016-11-22 修回日期:2017-03-01 发布日期:2017-03-03
  • 通讯作者: 陈河如 E-mail:thrchen@jnu.edu.cn
  • 基金资助:

    广东省自然科学基金（No.2015A030311012）和江西省自然科学基金（No.20151BAB215030）资助项目.

Design Synthesis of Gardenamide A/Tacrine Hybrids and Their Protection against 6-Hydroxydopamine-Induced Insults in PC12 Cells

Zhang Xinyia, Yuan Shenga, Zhao Jiaqianga, Zhang Leia, Zhang Chaoa, Wang Rikangb, Chen Herua,c   

  1. a. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632;
    b. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006;
    c. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632
  • Received:2016-11-22 Revised:2017-03-01 Published:2017-03-03
  • Contact: 10.6023/cjoc201611026 E-mail:thrchen@jnu.edu.cn
  • Supported by:

    Project supported by the Natural Science Foundation of Guangdong Province (No. 2015A030311012) and the Natural Science Foundation of Jiangxi Province (No. 20151BAB215030).

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补充材料

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设计合成了7个栀子酰胺A （GA）-他克林杂合物. 首先以京尼平为原料，经5步反应合成10-栀子酰胺A醛（DG），总收率20.4%；再以邻氨基苯甲酸甲酯为原料，经4步反应合成N-末端氨基烷基他克林（TN-n），总收率50.0%~65.4%；随后，DG与TN-n在合适的还原剂作用下还原胺化获得目标化合物，收率37%~54%. 所有目标产物的结构均由1H NMR，13C NMR和ESI-MS确证. 同时建立了六羟多巴胺（6-OHDA）诱导损伤的PC12细胞模型对系列杂合物进行生物活性评价. 发现杂合物TNG-1和TNG-5具有比他克林、GA及其联合用药更好的神经保护作用，推测这两个杂合物可能具有比单体药物更好的类药性.

关键词: 药物设计, 药物合成, 栀子酰胺A, 他克林, 阿尔茨海默病

Seven gardenamide A (GA)/tacrine hybrids have been designed and synthesized. Firstly, 10-gardenamide A (DG) aldehyde was prepared through 5 steps reactions applied genipin as starting material. The overyield was 20.4%. Then, N-terminated aminoalkyltacrine (TN-n) was synthesized via 4 steps reactions started from o-aminobenzoic acid. The overall yield was 50.0%~65.4%. After that, DG reacted with TN-n at the presence of appropriate reductant leading to the target compounds. The yields were from 37% to 54%. The structures of all the target compounds were confirmed by 1H NMR, 13C NMR and ESI-MS. The bioactivities of all the hybrids were evaluated by setting up 6-hydroxydopamine-induced impaired PC12 cell model. It was indicated that two hybrids TNG-1 and TNG-5 showed better neuroprotective activity than tacrine, GA or their combination. Based on this fact, it was proposed that the hybrids TNG-1 and TNG-5 were better drug-like candidates than both monomers.

Key words: drug design, drug synthesis, gardenamide A, tacrine, alzheimer disease