几种硫代糖及其衍生物的设计合成与活性研究
文献类型：学位论文
| 作者 | 毕晶晶 |
| 学位类别 | 博士 |
| 答辩日期 | 2015-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 杜宇国 |
| 关键词 | 硫代糖 寡糖合成 甘露三糖 簇合物 KRN7000 生物活性。Thiosugar Oligosaccharide synthesis Mannotriose Glucocluster KRN7000 Biological activity |
| 其他题名 | Design, Syntheses and Biological Evaluation of Thiosugar and their Derivatives |
| 学位专业 | 分析化学 |
| 中文摘要 |
本论文主要开展针对糖类化合物中以硫原子代替氧原子（包括环内与环外）后，这些化合物的合成方法及生物活性研究。全文共分为三章： 第一章综述了近年来糖化学中硫苷类化合物和硫杂糖类化合物的结构、合成及活性应用。 第二章 HIV糖蛋白gp120表面高密度的表达了高甘露糖型寡糖链，甘露三糖作为高甘露糖型寡糖的核心单位，具有非常重要的生物功能。如促进造血细胞增殖、降血糖、抗肿瘤、提高免疫力等作用。本章开展了相应的含硫苷的甘露三糖及其簇合物的合成与活性研究。以修饰的甘露糖施密特试剂为糖基供体，从甘露糖出发经过 11步以 11.1%的总收率得到含 6-硫甘露糖残基的硫代甘露三糖 2-38，并以中间体 2-56为原料经过 6步以 36.2%的总收率获得以均苯三甲酰氯为核心和氨基乙硫醇为连接臂的 C3对称簇合物 2-58。并对它们进行了血凝抑制性实验和分子对接模拟，结果表明甘露三糖氧苷中的连接氧被硫原子取代后形成的硫代甘露三糖及其簇合物仍然能与 Con A相结合，簇合物2-58的 抑制活性达到与阳性对照天然氧苷一样的水平，而单体 2-38则表现出稍微减弱的活性。 第三章 KRN7000具有多种生物学活性，如抗肿瘤、抗真菌、抗结核病等，能激活 NKT细胞并参与多种自身免疫性疾病、动脉粥状硬化和感染性疾病的免疫调节。本章以 5-硫-半乳糖施密特试剂和植物鞘氨醇为原料立体选择性地合成了 3个硫代 KRN7000类似物，并测定了它们的生物活性。免疫测试结果表明化合物 3-53和 3-54表现出比 KRN7000更好的分泌 IFN-γ活性，具有 Th1选择性。这些实验结果为我们发展新的有潜力的免疫刺激试剂提供了方向。 |
| 英文摘要 | This dissertation is focusing on the saccharide compounds by sulfur atoms instead of oxygen (including inside and outside the ring), with exploring synthesis and biological activities of these compounds. Three chapters are included in the thesis: In Chapter one, the recent advances of structure, synthesis, biological activities and utilities of thiooligosaccharide and the thiosugar containing 4-thio-furanose or 5-thio-pyranose were reviewed. The surface of HIV glycoprotein gp120 expresses high-mannose oligosaccharidewith high–density. As the core unit of high-mannose oligosaccharide, mannotriose has some important biological functions, such as anti-tumor, promoting proliferation of hematopoietic cells, regulating blood sugar level, enhancing immunity. In Chapter two, the synthesis and biological activity evaluation of corresponding thiomannotriose and trivalent cluster mannotriose were carried out. The S-glycosyl analogues of the core mannotriose, 6-S-linked trimannoside 2-38 was synthesized in 11 steps from mannose, with 11.1% yield. And trivalent cluster S-linked mannotriose 2-58 was synthesized in 6 steps from intermediate 2-56, with 36.2% yield. Hemagglutination inhibition of the two thiomannotriose analogues was examined, as well as the computational study with 2-38. The results showed that the new S-glycosyl analogue with linker sulfur atom could bind with ConA in the same way with the parent trimannoside. The cluster mannotriose 2-58 possessed the same inhibitory potency as that of the parent trimannoside, and the monomer 2-38 had a slight lower inhibition. KRN7000 has a variety of biological activities, such as anti-tumor, anti-fungal,anti-tuberculosis. It can activate NKT cells and participate in a variety of immune regulation of autoimmune diseases, atherosclerosis and infectious diseases. In Chapter three, three new KRN7000 S-sugar analogues were synthesized stereoselectively with 5-S-galactopyraosyl trichloroacetimidate and phytosphingosine as raw materials. Their abilities to stimulate the cytokine production of NKT cells were evaluated both in vivo and in vitro. In the testing, 5-thio-KRN7000 (3-53) and 5-thio-α-GalCer 566 (3-54) stimulated higher IFN-γ production than that of KRN7000. This results paved the way for developing new potent immunostimulating agents. |
| 源URL | [http://ir.rcees.ac.cn/handle/311016/34114]  |
| 专题 | 生态环境研究中心_环境化学与生态毒理学国家重点实验室 |
| 推荐引用方式 GB/T 7714 | 毕晶晶. 几种硫代糖及其衍生物的设计合成与活性研究[D]. 北京. 中国科学院研究生院. 2015. |
入库方式： OAI收割
来源：生态环境研究中心
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