新颖抗血小板活性松香烷二萜的结构优化与作用机制研究

血栓被称为“沉默的杀手”，严重威胁着人们的健康。抗血小板药是防治血栓性疾病的主要手段，出血倾向、药物抵抗、个体差异等缺陷制约着阿司匹林、氯吡格雷等临床首选药物的使用。因此，寻找有效防治血栓形成，降低出血风险的抗血小板药物仍迫在眉睫。鼠尾草属（Salvia）植物是我国治疗心脑血管疾病最著名的药用植物类群之一。前期围绕鼠尾草二萜类成分进行了抗血小板活性探索，首次发现一系列开环型松香烷二萜具有显著的抗血小板聚集活性，其中化合物Rxh-158活性比对照药物阿司匹林强25倍，且可显著抑制实验性大鼠颈动脉血栓的形成。进一步对Rxh-158进行了全合成和机制探索研究，为血小板抑制剂的研发奠定了基础。因此，本项目将围绕Rxh-158进行构效关系和结构优化研究、作用机制和靶点研究、及系统的体内抗血栓作用和出血倾向评估，以期获得结构新颖、活性显著、靶标明确的新型抗血小板先导分子。

Thrombosis is regarded as a "silent killer" and a serious threat to people's health. Antiplatelet drugs are the main means of clinical prevention and treatment of thrombotic diseases. The use of priority drug such as aspirin and clopidogrel are restricted due to bleeding tendency, drug resistance, individual differences and other defects. Therefore, it is urgent to find antiplatelet drugs that can effectively prevent and cure thrombosis and reduce the risk of bleeding. Salvia is one of the most famous medicinal plant groups for the treatment of cardiovascular diseases in China. The antiplatelet aggregation activity of Salvia diterpenoids were explored in the early stage. As a result, a series of seco-abietane diterpenoids possessed significant antiplatelet aggregation activity induced by arachidonic acid. Significantly, Rxh-158, the most potent one, was 25-fold better than the positive control aspirin, and showed efficacy in the rat ferric chloride thrombosis model. The total synthesis and preliminary mechanism of Rxh-158 were studied, which laid a foundation for the development of anti-platelet inhibitors. Therefore, this project will further study the structure-activity relationship, mechanism and target, the efficacy on antithrombotic effect in vivo of Rxh-158, as well as a safety profile in the rat surgical blood loss model. Finally, we hope to obtain a new type of antiplatelet lead molecule with novel structure, significant activity and clear target.