三类活性天然萜类化合物的化学合成及结构修饰研究

	三类活性天然萜类化合物的化学合成及结构修饰研究
	颜秉超
导师	普诺·白玛丹增
关键词	萜类化合物 terpenoids, structural modification, immunosuppression, lysosomal biosynthesis, chemical synthesis 结构修饰免疫抑制溶酶体生成化学合成
摘要	本报告由四章组成。第一章论述了对具有6/6/4骨架杂二萜 isoscopariusin A开展的结构修饰和生物活性研究。基于isoscopariusin A 两代合成路线，采取结构简化策略合成了90个结构衍生物，从中发现多个对 T、B淋巴细胞具有良好免疫抑制活性的结构修饰物，选择指数优于原型天然产物。同时还发现PYL-66等化合物具有显著促进溶酶体生成活性，能够激活主导溶酶体合成的TFEB转录活性。第二章论述了一类新型复杂环丙烷衍生物的合成方法及其T型钙通道调节活性。新合成骨架化合物2-19对T型钙通道Cav3.1具有显著的抑制作用，首次发现2-11和2-23分别对T型钙通道Cav3.1和Cav3.2具有选择性失活调节作用。第三章和第四章分别介绍了通过合作完成的新颖天然二萜maoericalyxin E的首次仿生合成和新颖骨架倍半萜二聚体henryinins A-E 的首次全合成。以高含量天然产物毛萼乙素为起始原料以所发展的wolf重排串联内酯化为关键反应构建了手性5/6双环，完成了二萜maoericalyxin E 的10步仿生合成，解决了天然分子的构型确证难题。采取发散式合成策略，以商业可得光学纯右旋香芹酮为起始原料，以 Robinson增环和Diels Alder为关键反应首次实现5个倍半萜二聚体的无保护全合成。以上研究对于深入挖掘新颖天然产物及其衍生物的潜在生物功能具有重要研究意义，为新型药物先导化合物发现奠定了坚实的研究基础。; This report consists of four chapters. The first chapter discusses study of structural modification and biological activities of isoscopariusin A with a 6/6/4 skeleton. Based on the two generation synthetic routes of isoscopariusin A, we adopted a structure simplification strategy to synthesize ninety derivatives, among of which a number of structural modifiers displayed immunosuppressive activity on T and B lymphocytes, with better selection index SI than that of isoscopariusin A . Biological activity study disclosed that PYL-66 significantly promoted the formation of lysosomes and activated the transcriptional activity of TFEB, dominating the biosynthesis of lysosomes. The second chapter descibes the synthesis of a new type of complex cyclopropane derivatives and their T type calcium channel activity. The synthesized 2-19 with novel scaffold have a significant inhibitory effect on the T type calcium channel CaV 3.1. For the first time, we found that 2-11 and 2-23 have selective inhibitory and modulatory effects on the T type calcium channel CaV 3.1 and CaV 3.2, respectively. Chapters 3 and 4 respectively introduce the first biomimetic synthesis of a novel natural diterpenoid maoericalyxin E and the first total synthesis of sesquiterpenoid dimers with novel skeletons, henryinins A-E. A 10-step biomimetic synthesis of maoericalyxin E was accomplished starting from a high content natural product maocalyxin B, through the developed wolf rearrangement tandem lactonization as the key reaction to construct a chiral 5/6 scaffold. The synthesis facilitated the configuration confirmation of maoericalyxin E. The first protecting group free total synthesis of henryinins A-E were achieved in a divergent synthesis strategy from commercially available optically pure D-(+)-carvone featuring Robinson ring enlargement reaction and Diels Alder reaction as the key steps. These studies have important research significance for deeply exploring the potential biological functions of the new types of natural products and their derivatives, and have laid a solid research foundation for the discovery of new drug leads.
语种	中文
	2022-01
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/151853/75087
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	颜秉超. 三类活性天然萜类化合物的化学合成及结构修饰研究[D]. 中国科学院大学,2022.

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