鼠尾草属植物中裂环-松香烷二萜类新型血小板聚集抑制剂的研究

安全、高效的新型抗血小板先导分子是抗血栓新药研发的重点；从药用植物中发掘先导分子是新药研发的重要途径。鼠尾草属植物是治疗心脑血管疾病最著名的传统药用植物类群之一。申请人长期从事鼠尾草二萜类成分研究，先后发现并报道了大量结构新颖、活性显著的二萜化合物。近期首次发现系列裂环-松香烷二萜类化合物能选择性抑制AA诱导的兔血小板聚集，部分化合物活性强于阳性对照阿司匹林；且可显著抑制实验性大鼠颈动脉血栓的形成。在此基础上，本项目拟以抗血小板活性为线索，进一步开展富含裂环-松香烷的雪山鼠尾草中目标成分的针对性挖掘；同时通过结构修饰与优化制备系列衍生物；并评价其抗血小板活性；以阐明其构效关系；继而选择活性显著的化合物进行作用机制与体内抗血栓活性研究；以期获得结构新颖、活性显著、机制和靶点明确的新型血小板聚集抑制剂，为抗血栓创新药物的研发提供理论基础与先导分子。

The discovery of safe and efficient new antiplatelet leading compounds is the focus of the research and development of new antithrombotic drugs. The exploration of lead compounds from the plants with relevant medicinal background is one of the important approaches for new drug research and development. Distributed widely in the Hengduan Mountains in the southwest of China, the plants Salvia have been used as one of the most famous traditional medicines against cerebrovascular diseases. Diterpenoids, especially abietane type diterpenoids with diverse structures and intriguing bioactivities are the typical constituents of Salvia plants. Most of the researches on Salvia have been focused on its bioactive constituents for anticancer and antibacterial, etc. Apparently, further research about the active constituents from Salvia would prove valuable data for their medicinal usage..We have systematically studied the diterpenoid constituents from Salvia plants since 2000, and have made some important progress in the phytochemical investigation of abietane type diterpenoids with diverse chemical structures as well as their important bioactivities. Notably, a series of seco-abietanes from S. prattii (which was collected in the high altitude area in Hengduan Mountains) have been found to exhibit significant bioactive of anti-platelet aggregation. Based on this interesting observation, this project will carry out a systematic LC/UV guided isolation of the seco-abietane diterpenoids from Salvia evansiana which also collected in the Hengduan Mountains with high altitude (4000 m). And then, series of derivatives will be synthetized by the structural modification. In addition, systematic studies of their anti-platelet aggregation bioactive in vitro and in vivo together with the mechanism studies, will conduct to find the suitable lead compounds for further researches. This work will promote the research progress of natural diterpenoid constituents from Salvia, and provide new lead compounds with promising anti-platelet aggregation properties for the research and development of new drugs with independent intellectual property.