四种石松科植物新型生物碱成分及其抗阿尔茨海默症活性研究

项目名称： 四种石松科植物新型生物碱成分及其抗阿尔茨海默症活性研究

项目编号： No.21472021

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境科学、安全科学

项目作者： 胡金锋

作者单位： 复旦大学

项目金额： 90万元

中文摘要： 石松蕨类植物广含结构独特的石松生物碱。部分石松生物碱因其天然高选择性抗乙酰胆碱酯酶活性，成为近年来的研究热点之一。课题组从我国不同地区采集了四种石松科植物（毛枝垂穗石松、笔直石松、多穗石松及扁枝石松），这几种国产石松植物的生物碱成分还未得到研究抑或研究不够深入。初筛时发现它们的生物碱总提物均具有抗AChE活性，且初步的化学成分分析揭示这些总提物都含有不同于石杉碱甲骨架的化合物。基于此，本申请项目拟对这四种植物生物碱成分开展系统的研究，以期发现一批结构新颖（特别是有别于石杉碱甲的新骨架）的化合物；针对多个与阿尔茨海默症相关的细胞筛选模型对单体化合物的抗AChE、激动M1受体、神经损伤保护及神经抗炎等活性进行评估，对筛选得到的活性成分展开相关作用机制研究；对部分分离量较大的活性化合物开展衍生物库的制备，并进行构效关系探讨。研究成果将为从石松科植物中开发出更有效更安全的新型抗AD药物奠定基础。

中文关键词： 石松科植物；生物碱；新颖结构；阿尔茨海默病；作用机制

英文摘要： The Lycopodium alkaloids (LAs) are a structurally related, yet diverse group of compounds, originally isolated from the Lycopodium plants. Due to their highly selective anti-AChE activities and unique structural characteristics, LAs have attracted great attention of many natural product chemists and organic synthetic chemists. Recently, we have successfully collected four Lycopodiaceae plants from different locations of China. These include previously unexplored Lycopodium obscurum f. strictum and Palhinhaea cernua f. sikkimensis, and also include much less studied Lycopodium annotinum and Daphasiastrum complantum. We found that all the alkaloid-containing extracts from the above plants exhibited anti-AChE activities. Moreover, the alkaloids from those extracts were detected to possess different carbon skeletons other than huperzine A (lycodine-type) according to our preliminary chemical analyses. In this project, we propose to carry out a more systematic investigation on the LAs-related constituents from the aforementioned crude extracts, highly likely culminating in the identification of a series of alkaloids with novel scaffolds. Thereafter, the purified alkaloids will be evaluated for their anti-Alzheimer's Disease (AD) activities by assessing their anti-AChE, selective M1 receptor agonist, neuro-protective and anti-neuroinflammative effects. The anti-AD mechanisms of the active compounds will be further studied. Chemical derivatives of the identified major bioactive compound(s) will be prepared for SAR studies. The results will be of great significance for the development of new, safe and effective anti-AD drug candidate(s) from Lycopodiaceae plants.

英文关键词： Lycopodiaceae Plants;Alkaloids;Novel Skeletons;Alzheimer's Disease;Mechanisms