四种中国特有金粟兰属植物中新颖萜类化学成分的发现及其结构与生物功能研究

Our previous phytochemical studies on Chloranthus plants have shown that this genus is rich in diterpenoids and sesquiterpenoids with novel and fantastic frameworks, some of which were found to exhibit significant anti-neuroinflammatory activities by inhibiting the over-release of nitric oxide (NO) and tumor necrosis factor alpha (TNF-α) in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and/or to show significant inhibitory effects against the human protein tyrosine phosphatase 1B (PTP1B) enzyme. In fact, the above mentioned neuroinflammation and PTP1B both have been regarded to be implicated in the pathogenesis and processes of neurodegenerative disorders, such as Alzheimer’s disease (AD). Based on these findings, we herein propose to carry out a more systematic investigation on another four rare Chloranthus species endemic to China, i. e., C. holostegius var. trichoneurus, C. sessilifolius var. austrosinensis, C. henryi var. hupehensis, and C. multistachys. The selected rare plants have never or seldom been chemically or pharmacologically investigated, highly likely culminating in the identification of a series of diterpenoids/sesquiterpenoids with novel scaffolds. The isolates will be subjected to the well-established bioassay protocols to determine their anti-neuroinflammtory and PTP1B inhibitory activities. The novel Mechanisms of Action (MOA) and related signal pathways of the desired compounds will be further studied. Novel anti-neuroinflammatory and particularly the “bifunctional” (i.e., possessing both the inhibitory effects against neuroinflammation and the PTP1B enzyme) lead compounds can be potentially used as a new strategy for the medical therapy of neurodegenerative disorders. Chemical derivatives of the identified major bioactive compound(s) will be prepared for structure-activity relationship (SAR) studies. The results will not only greatly enrich our in-depth, systematic research of chemical components (terpenoids in particular) from Chloranthus plants endemic to China, but also will be of great significance for the discovery and development of novel lead compound(s) for the treatment of neurodegenerative diseases (e.g., AD).

研究表明小胶质细胞过度活化介导的神经炎症反应和蛋白酪氨酸磷酸酯酶1B (PTP1B) 均与神经退行性疾病（如AD）的发生、发展有着密切关系。前期研究发现金粟兰属植物富含新颖二萜及倍半萜，且其中部分化合物能显著抑制上述神经炎症反应和/或PTP1B酶活性。本项目拟对目前尚未研究或研究较少的我国特有的四种稀有金粟兰植物（毛脉、华南、湖北和多穗金粟兰）的二萜/倍半萜类特征次级代谢产物进行系统研究，分离和鉴定一批新结构（含新骨架）。对单体化合物进行抗神经炎症和PTP1B抑制活性筛选，进而开展具体作用靶标及调控网络研究，希冀从中发现对神经退行性疾病具有潜在治疗作用的抗神经炎症活性化合物以及“神经炎症/PTP1B双重抑制”活性小分子。对部分分离量较大的活性化合物开展衍生化和构效关系探讨。研究成果将极大丰富我国金粟兰属植物萜类化学成分，并为从中开发出新型治疗神经退行性疾病的药物先导化合物提供科学依据。

萜类成分的研究一直是天然药物化学领域最为活跃的领域之一，是寻找和发现新型天然药物先导化合物的重要来源（如明星分子青蒿素、紫杉醇等）。金粟兰科金粟兰属植物民间药用价值高（如中药及己），因其富含骨架类型多样、结构新颖的萜类成分，其相关研究一直备受关注。.基于此，在NSFC基金资助下，本项目选取了几种化学成分及其活性还未得到研究抑或研究不够深入的中国特有金粟兰属植物（华南金粟兰、毛脉金粟兰、湖北金粟兰、多穗金粟兰）以及立项后额外补充的另外一种稀有种——狭叶金粟兰作为研究对象，深入系统地开展了化学成分及其结构与生物功能研究。从上述5种金粟兰属植物中累计分离并鉴定单体化合物140余个（其中138个为倍半萜/二萜成分），新骨架2类、新化合物37个。对所分离得到的萜类化合物围绕神经抗炎、PTP1B抑制等多种生物活性开展了评价。目前已发现shizukaol C等10个化合物表现出较强的抗神经炎症活性，进而以shizukaol C为探针分子，开展了其抑制TMAO诱导的VSMCs黏附作用机制研究。. 本研究成果不仅较大程度地丰富和扩充了我国金粟兰属植物中萜类成分的研究内容和结构类型，为从化学分类学角度对金粟兰属植物进行分类鉴定以及厘清本属植物倍半萜成分的生源相关性提供更多科学依据，同时（也是更重要的是）为金粟兰属药用植物及其萜类成分的药用开发提供了一定的参考价值并打下坚实基础。