FCS三糖衍生物的合成及抗凝血活性评价

	FCS三糖衍生物的合成及抗凝血活性评价
	李碧媛
导师	秦红波
关键词	长碳链寡糖，糖苷化反应，click化学，岩藻糖基化的硫酸软骨素 Long carbon chain oligosaccharide, Glycosylation reaction, Click chemistry, Fucosylated chondroitin sulfate
摘要	FCS(Fucosylated Chondroitin Sulfate)是海参中一种独特的多糖，被命名为岩藻糖基化的硫酸软骨素，它的主链是由葡萄糖醛酸(GlcA)和N-乙酰氨基半乳糖(GalNAc)通过β(1→3)糖苷键连接而成，支链则是在硫酸软骨素的其余位点通过连接L-岩藻糖(L-Fuc)构成。大量研究表明，FCS具有广泛的生物活性，如抗血栓、抗凝血、抗癌、抗病毒、促进血管生成、调节免疫和细胞生长等作用，并且其抗凝血、抗血栓的作用要优于肝素(UFH)、低分子量肝素(LMWH)和硫酸皮质素(DS)。本论文主要针对FCS三糖衍生物的合成展开基础性研究。经过大量的探索，最终我们成功将叠氮和炔烃引入FCS三糖的还原端。该工作为进一步开发岩藻糖胺聚糖作为抗凝血药物提供了基础。论文包括以下两个部分：第一章主要描述了低聚糖合成的研究现状以及合成过程中面临的主要问题和挑战。我们从研究现状了解到糖苷化反应的反应条件、反应策略、寡糖分子的立体构型以及保护基的性质等均是影响糖苷化反应合成效率极其重要的因素，因此，我在这一章里描述了糖分子的保护基策略、糖苷键形成策略以及近些年来硫酸软骨素（CS）和岩藻糖基化的硫酸软骨素（FCS）的研究现状；另外，我们还综述了点击化学近年来在糖分子的合成中的应用。第二章主要描述了对FCS三糖衍生物的合成研究。我从研究现状出发优化了FCS三糖的合成路线，在这个过程中，由于烯丙基保护基非常稳定，我们没有找到经济适用且方便高效的脱保护方法，因此，为了FCS三糖的高效合成和后续官能团转化的便捷，我们通过探索并最终确定了双亚甲基萘的保护、脱保护方法，这个保护基的使用有效提高了FCS三糖的合成效率、有利于后续的官能团转化反应；具体如下：利用三氯乙酰亚胺半乳糖（Schmidt）供体2-45和双亚甲基萘葡萄糖受体2-59合成二糖2-60，随后经2步反应得到二糖受体2-62，最后与岩藻糖供体2-6连接得到FCS三糖2-8，汇聚合成路线共26步，总收率3.5%；其次，在得到目标三糖之后，实现了三糖还原端不同取代基保护的FCS三糖合成，分别完成了Schmidt三糖供体2-64、乙酰三糖供体2-65、苯乙烯苯甲酸（PVB）供体2-66、炔基三糖2-67以及叠氮三糖2-68的合成。其中最重要的是，我首次合成了2-67和2-68，解决了FCS三糖还原端无法引入炔基的问题，具体如下：首先，利用Schmidt供体2-45、葡萄糖受体2-72完成了二糖2-73的合成，随后在DDQ的条件下脱去2,3-Nap、并且利用苯甲酸酐和三乙胺选择性保护2-OH得到二糖受体2-75，最后和岩藻糖供体2-6反应得到三糖2-67，汇聚合成路线26步，总收率为1.02%；随后，我们利用类似的方式完成了FCS叠氮三糖2-68的合成，总收率为0.73%。以上进展为FCS寡糖的合成提供了新颖的保护基选择，有利于衍生物的制备，为进一步研究具有抗凝血作用的FCS寡糖提供了良好的参考。; FCS (Fucosylated Chondroitin Sulfate) is a unique polysaccharide in sea cucumber, named fucosylated chondroitin sulfate. Its main chain is composed of glucuronic acid (GlcA) and N- acetylgalactosamine (GalNAc) linked by β (1→3) glycosidic bond, and its branch chain is linked by L- fucose (L-Fuc) at the rest sites of chondroitin sulfate. A large number of studies have shown that FCS has a wide range of biological activities, such as anti-thrombosis, anti-coagulation, anti-cancer, anti-virus, promoting angiogenesis, regulating immunity and cell growth, and its anti-coagulation and anti-thrombosis effects are better than those of heparin (UFH), low molecular weight heparin (LMWH) and corticosteroid sulfate (DS). This paper mainly focuses on the basic research of the synthesis of FCS trisaccharide derivatives. After a lot of exploration, finally we successfully introduced azide and alkyne into the reducing end of FCS trisaccharide. This work provides a basis for further development of foundation as anticoagulant.. The thesis includes the following two parts: The first chapter mainly describes the research status of oligosaccharide synthesis and the main problems and challenges in the synthesis process. From the research status, we know that the reaction conditions, reaction strategies, the three-dimensional configuration of oligosaccharide molecules and the properties of protective groups are all extremely important factors that affect the synthesis efficiency of glycosylation. Therefore, in this chapter, I describe the strategies of protective groups and glycosidic bond formation of sugar molecules, and the research status of chondroitin sulfate (CS) and fucosylated chondroitin sulfate (FCS) in recent years. In addition, we also reviewed the application of click chemistry in the synthesis of sugar molecules in recent years. The second chapter mainly describes the synthesis of FCS trisaccharide derivatives. I optimized the synthesis route of FCS trisaccharide from the present research situation. In this process, because the allyl protecting group is very stable, we didn't find an economical, convenient and efficient deprotection method. Therefore, in order to efficiently synthesize FCS trisaccharide and facilitate the subsequent functional group conversion, we finally determined the protection and deprotection method of dimethylnaphthalene through exploration. The use of this protecting group effectively improved the synthesis efficiency of FCS trisaccharide and was beneficial to the subsequent functional group conversion reaction. Specifically, disaccharide 2-60 was synthesized from trichloroacetylimine galactose (Schmidt) donor 2-45 and dimethylene naphthalene glucose receptor 2-59, then disaccharide receptor 2-62 was obtained by two steps of reaction, and finally FCS trisaccharide 2-8 was obtained by connecting with fucose donor 2-6. The total yield was 3.5% through 26 steps of convergent synthesis. Secondly, after the target trisaccharide was obt
语种	中文
	2022-05
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/151853/75130
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	李碧媛. FCS三糖衍生物的合成及抗凝血活性评价[D]. 中国科学院大学,2022.

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