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

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.

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。

石松蕨类植物广含骨架独特且结构多样的石松生物碱类化合物（LAs）。部分石松生物碱（如石杉碱甲）因其天然高选择性抑制乙酰胆碱酯酶（AChE）等活性而有望开发成为治疗阿尔茨海默症（AD）的新型药物，在国内外引起高度关注。.基于此，在本NSFC项目的资助下，我们选取了几种生物碱成分及其活性还未得到研究抑或研究不够深入的国产石松科蕨类植物（多穗石松、笔直石松、扁枝石松和毛枝垂穗石松）作为研究对象，对其中的石松生物碱成分及其多靶点抗AD活性开展深入系统的研究。不仅如此，为进一步扩充石松生物碱的结构多样性和利于构效关系的探讨，我们在上述项目书中所涉四种石松植物的基础上，后陆续对其他两种近缘植物（垂穗石松和金丝条马尾杉）亦开展了相关研究。从这些石松蕨类植物中累计共分离并鉴定目标生物碱类化合物127个，其中新化合物36个（含新骨架5个）。同时，针对AD相关治疗靶点（主要包括抗AChE活性、抗Aβ聚集、神经损伤保护及神经抗炎活性等），对上述LAs开展了广泛的活性测试。部分化合物表现出较强的抗AChE或抗Aβ聚集活性，亦体现出一定的构效关系（SAR），为基于该类生物碱结构的新型抗AD药物研发提供了新的线索和科学依据。.综上，本项目研究成果不仅较大程度地丰富和扩充了我国石松蕨类植物中生物碱成分的研究内容和结构类型，为从化学分类学角度对该类植物进行分类鉴定提供更多科学依据；同时更为重要的是为基于石松生物碱类结构的多靶点抗AD新型药物研发提供了一定的参考价值并打下坚实基础。.