抗血小板活性松香烷二萜的合成、结构优化及机制研究

	抗血小板活性松香烷二萜的合成、结构优化及机制研究
	夏凡
导师	许刚
关键词	康定鼠尾草，松香烷二萜，抗血小板活性，合成和结构优化研究 Salvia prattii, Abietane diterpenoid, Antiplatelet aggregation activity, Synthesis and structure optimization
摘要	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。本报告围绕康定鼠尾草 (S. prattii) 中抗血小板活性松香烷二萜的发现，活性分子的合成、结构优化，抗血小板作用机制探究展开，分为三部分内容。 (1) 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14个松香烷型二萜对AA诱导的兔血小板聚集具有显著而强效的抑制作用。其中， Rxh-158和Rxh-185的抗血小板聚集活性最显著，其抑制AA诱导的兔血小板聚集的IC50 分别为1.03 和2.15 μg/ml，抑制活性比对照药物阿司匹林 (IC50为27.69 μg/ml) 强约25倍。体内抗血栓活性显示，Rxh-158和Rxh-185在FeCl3诱导损伤的大鼠颈动脉血栓模型中可以显著延长动脉血管阻塞时间。进一步研究表明，Rxh-158对不同的信号分子激动剂活化血小板均有显著的抑制活性，可能具有类似DAPT药物联用的优势药效特征。（2）对Rxh-158 进行了全合成研究，以苯并环己酮为起始原料，经过傅克烷基化、Wacker氧化、烷基化等关键反应，9步5.6%的总收率首次合成了Rxh-158。以丰产天然产物ferruginol为起始底物，经烯丙位氧化、开环重排等关键步骤，6步12.8%的总收率合成了Rxh-185。（3）围绕Rxh-158进行了构效关系和结构优化研究，合成了Rxh-158的结构衍生物65个，初步阐明了Rxh-158的构效关系，并设计合成了一系列酯、酰胺、苯胺类衍生物，发现了部分抗血小板活性分子。; Thrombosis was regarded as a ‘silent killer’ and a serious threat to people’s health. Antiplatelet drugs were the main means of clinical prevention and treatment of thrombotic diseases. The use of priority drugs such as aspirin and clopidogrel were 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. This dissertation mainly discussed the discovery of antiplatelet active abietane diterpenoids from S. prattii, as well as the synthesis, structure optimization, and mechanism of abietane-type platelet aggregation inhibitors, including three chapters. (1) The antiplatelet aggregation activity of 110 abietane diterpenoids were evaluated, 14 compounds possessed significant antiplatelet aggregation activity induced by arachidonic acid (AA). Significantly, Rxh-158 and Rxh-185 showed the most excellent antiplatelet aggregation activity, with IC50 values 1.03, 2.15 μg/ml, respectively, which were approximately 25-fold better than the positive control aspirin (IC50 27.69 μg/ml), and showed efficacy in the rat ferric chloride thrombosis model. Further studies showed that Rxh-158 had significant inhibitory activities against platelets activated by different signaling molecule agonists, and the broad spectrum antiplatelet activity of Rxh158 might make it have the superior pharmacodynamic characteristics similar to DAPT combination. (2) The synthetic studies of Rxh-158 were carried out, which abotined from benzocyclohexanone through key reactions such as Friedel-Crafts alkylation, Wacker oxidation and alkylation reaction in a total yield of 5.6% in 9 steps. What’s more, Rxh-185 was synthesized from ferruginol with 12.8% total yield in 6 steps through allylic oxidation and rearrangement. (3) The structure-activity relationship and structure optimization of Rxh-158 were studied. Sixty-five derivatives were synthesized and the structure-activity relationship of Rxh-158 was preliminarily clarified. What’s more, a series of lactones, amides and anilines derivatives were designed and synthesized.
语种	中文
	2022-04
学位授予单位	中国科学院大学
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75100
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	夏凡. 抗血小板活性松香烷二萜的合成、结构优化及机制研究[D]. 中国科学院大学,2022.

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