泽泻醇Alisols A/B的结构修饰与石松生物碱Huperserratines A/B的全合成研究

	泽泻醇Alisols A/B的结构修饰与石松生物碱Huperserratines A/B的全合成研究
	邓振涛
导师	赵勤实
关键词	泽泻醇 B，NAFLD，石松生物碱，Huperserratine A，全合成 Alisol B, NAFLD, Lycopodium alkaloids, Huperserratine A, Total synthesis
摘要	摘要本论文由三章组成，第一章介绍了泽泻醇A/B的结构修饰与构效关系研究；第二章介绍了蛇足石杉中石松生物碱的分离与鉴定和化合物huperserratine A和B的首次全合成研究；第三章综述了近五年来石松生物碱全合成的研究进展。第一章泽泻醇B的结构修饰与构效关系研究非酒精性脂肪肝病（non-alcoholic fatty liver disease，NAFLD）是指除酒精和药物、遗传疾病等其他明确因素之外所致的肝脏脂肪变性和肝脏脂肪过度蓄积为特征的病征。在中国，成年人中NAFLD患病率约30%，而在肥胖和糖尿病群体中的患病率可达70%。NAFLD已成为威胁全球健康的公共卫生问题，其发病机制涉及到多种因素，是一个复杂的过程，因此，有效的治疗方法十分有限。目前临床上主要通过饮食干预和运动疗法来防治脂肪肝，并没有针对NAFLD的特效药。泽泻是中国传统中药，原萜烷型三萜为该属植物所特有，经大量研究发现，泽泻提取物及三萜类活性成分具有治疗NAFLD的活性。我们从泽泻的主要成分alisol B和其代谢产物alisol A出发，在其结构的六个位点上，设计合成衍生物62个，经两种细胞模型筛选出10个对NAFLD活性较好衍生物，再经大鼠模型筛选出2个表现较好的化合物。经过对泽泻醇A/B的结构修饰与构效关系研究，初步探明了各官能团的修饰方法与治疗NAFLD的活性的关系，为泽泻中高含量的泽泻醇B的进一步开发打下了坚实的基础。第二章石松生物碱的化学成分与全合成研究石松生物碱huperserratine A和B是我们课题组2020年从蛇足石杉（Huperzia serrata (Thunb.) Trev.）中分离得到的一对异构体，是迄今发现的第一例具有双环[10.4.0]十六烷骨架的大环石松生物碱，并且具有罕见的肟官能团。我们对蛇足石杉的化学成分再次研究，顺利得到了huperserratine A和B和其他7个化合物，包括5个新化合物。由于这两个化合物在植物中含量较少，为了便于对它们的继续研究与开发，我们又从已知化合物(5R)-2-Iodo-5-methyl-2-cyclohexen-1-one出发，经Suzuki-Miyaura偶联，Michael加成，烯烃复分解等关键反应形成关键的双环[10.4.0]十六烷骨架。然后再经过双羟基化，Swern氧化，肟化反应等一共12步首次完成了目标分子huperserratine A和B的全合成。首次的合成工作不仅为这两个新颖化合物的进一步研究工作打下基础，并为lycopodine，fawcettimine等其他石松生物碱的合成打开了新的思路。第三章石松生物碱的全合成研究进展综述了石松生物碱从2017年至2022年5月五年间的全合成研究进展，17个课题组报道了19条不同的研究路线完成了43个石松生物碱的全合成工作。希望可以为石松生物碱的全合成研究提供一定参考。; Abstract This thesis consists of three chapters. The first chapter introduces the structure modification and structure-activity relationship of alisol B; The second chapter introduces the isolation and identification of Lycopodium alkaloids from Huperzia serrata and the first total synthesis of huperserratine A and B; The third chapter reviews the research progress of total synthesis of Lycopodium alkaloids in the past five years. Chapter 1 Structural modification and structure-activity relationship of alisol B Non-alcoholic fatty liver disease (NAFLD) is a disease characterized by hepatic steatosis and excessive accumulation of hepatic fat except other definite factors such as alcohol, drugs, and genetic diseases. In China, the prevalence of NAFLD in adults is about 30%, while the prevalence in obese and diabetic groups can reach 70%. NAFLD has become a public health problem that threatens global health. The pathogenesis of NAFLD involves many factors and is a complex process. Therefore, effective treatment methods are very limited. At present, dietary intervention and exercise therapy are mainly used to prevent and treat fatty liver in clinical practice, and there is no specific drug for NAFLD. Alisma orientalis is traditional Chinese medicine, and the protostane triterpenes are unique to this genus. A large number of studies have found that the extracts of Alisma orientalis and the active components of triterpenes have the activity of treating NAFLD. Starting from the main component of Alisma orientalis alisol B and its metabolite alisol A, we designed and synthesized 62 derivatives on the six sites of its structure, and screened out 10 derivatives with better NAFLD activity through two cell models. Then, two compounds with better performance were screened out by rat model. Through the study on the structure modification and structure-activity relationship of alisol A/B, the relationship between the modification method of each functional group and the activity of treating NAFLD was preliminarily proved, which laid a solid foundation for the further development of alisol B with high content in Alisma orientalis. Chapter 2 Chemical constitiuents and total synthesis of lycopodium alkaloids Lycopodium alkaloids huperserratine A and B are a pair of isomers isolated by our research group from Huperzia serrata (Thunb.) Trev. in 2020 and the first example of macrocyclic Lycopodium alkaloids with bicyclo[10.4.0]hexadecane skeleton and a rare oxime functional group. We re-studied the chemical constitiuents of Huperzia serrata, and successfully obtained huperserratine A and B and 7 other compounds, including 5 new compounds. Since these two compounds are less in the plant, in order to facilitate their continued research and development, we started from the known compound (5R)-2-Iodo-5-methyl-2-cyclohexen-1-one, and formed the key bicyclo[10.4.0] hexadecane skeleton through key reactions such as Suzuki-Miyaura coupling, Michael addition, and ring-closing
语种	中文
	2022-06
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/151853/75143
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	邓振涛. 泽泻醇Alisols A/B的结构修饰与石松生物碱Huperserratines A/B的全合成研究[D]. 中国科学院大学,2022.

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