四种高含量天然产物的化学及生物功能研究

	四种高含量天然产物的化学及生物功能研究; Chemical and Biological Function Exploration of Four High-content Natural Products
	周元飞
导师	普诺·白玛丹增
摘要	Abstract K.C. Nicolaou mentioned more than 30 molecules in the book, “Molecules that changed the world”, most of which are natural products. Most of the natural products mentioned in the book have two characteristics, one is the high content of natural products from natural sources, and the other is having excellent biological functions. In the development of natural products, the function of high-content natural products has been ignored to a certain extent. Therefore, how to use high-content natural products to carry out subject research is the core of our thesis. This thesis is composed of five chapters. The first chapter introduces the structural determining process of the high-content natural product beauverolide Ka (BVKA) isolated from an endophytic fungus beauveria sp., providing new ideas for the structural confirmation of the series of 7 new compounds and solving configurational problems of this type compounds over the past 40 years. The protective activity on HEI-OC1 cells and the ability to promote glucose uptake by muscle cells have been evaluated. The second chapter describes the biological research, probe synthesis and target identification of the high-content natural product nigranoic acid (NgA), which is ubiquitous in the Schisandraceae plants. The synthesized active probe Sbn-76 can directly binds the E2 ubiquitination ligase UbcH5b. Subsequent pharmacological experiments have also proved that the target of NgA is UbcH5b, and can further inhibit lapatinib induced autophagy and improve the sensitivity of triple-negative breast cancer (TNBC) cells to lapatinib. In addition, NgA is the first non-covalent inhibitor of UbcH5b reported so far. Chapter 3 illustrates the biomimetic synthesis of the new skeleton compound (–)-maoelactone A (MaoA) providing inspiration for the structural modification of the high-content natural product Oridonin (Orid) derived from Isodon rubescens. MaoA was successfully semi-synthesized through 10 step reactions, and the key Wolff rearrangement/lactonization cascade (WRLC) reaction was found to construct the 1,10-seco-2,20-abeo-1,20 lactonization skeleton in one step. The reaction mechanism of WRLC is explained by computational chemistry methods. The structural modification products of Orid derived from skeleton hopping inspriration were evaluated on anti-SARS-COV-2 and anti-tumor activities. Among them, compound 3-70 showed strong inhibitory activity against live viruses, with an EC50 value at 19±1 nM and TI value greater than 1000, both stronger than the positive drug remdesivir. Chapter 4 depicts the structural modification study of eriocalyxin B, a high-content natural product derived from I. eriocalyx on anti-tumor activity, and discovered 4-38 as a potent anti-ovarian cancer agent and its mechanism is being further explored. Chapter 5 summarizes the current status of covalent drugs and the development prospects of natural product covalent inhibitors. This thesis adopts the multidisciplinary integratio
	2021-11
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74586
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	周元飞. 四种高含量天然产物的化学及生物功能研究, Chemical and Biological Function Exploration of Four High-content Natural Products[D],2021.

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