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题名: 负载唾液酸碳苷磁性纳米粒子及活性天然产物的合成研究
作者: 张朝立
学位类别: 博士
答辩日期: 2013
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: 唾液酸 ; Sialic acid ; 糖基化磁性纳米粒子 ; Glyconano particles ; 天然产物全合成 ; Total synthesis of natural products ; Pyrenolide D ; Pyrenolide D ; Ribisin A ; Ribisin A
其他题名: Synthesis of Neu5Ac-C-galactopyranosyl-functionalized Magnetic Nanoparticles and Bioactive Natural P
中文摘要:
      糖是自然界最丰富的生物分子,它参与到许多生理过程中,例如细胞的信息传导、免疫应答、受精、细胞凋亡和感染等。因为糖化合物具有重要生理功能,它成为生物学和医学研究领域的热点。并且,以寡糖化合为基础的药物研究也已逐步发展起来。另外,糖是含有手性多羟基的醛、酮化合物,这使得它能够作为天然手性模板应用于手性天然产物的合成中,并简化合成路线。 论文涉及糖基化纳米粒子研究综述、负载唾液酸碳苷磁性纳米粒子的合成以及两个活性天然产物的全合成研究。全文共分为四章。 第一章对近年来关于糖基化纳米粒子的合成方法、表征方法及其应用的研究进展进行概述。近年来,纳米材料和纳米技术蓬勃发展,取得了丰富的研究成果。其中,糖基化纳米粒子作为纳米材料家族的一个分支,随着新方法和新技术的不断发展,展现出了优越的应用前景,特别是在医药和生物等研究领域,吸引着科学家的目光。 第二章详细总结了负载唾液酸碳苷磁性纳米粒子的合成研究成果。其中包括合成路线设计、实验步骤以及对所合成的寡糖化合物和纳米粒子的表征。唾液酸碳苷的合成利用SmI2促进的Barbier偶联反应来实现。Fe3O4磁性纳米粒子采用多元醇热还原法制备,并通过表面包裹硅胶层对金属纳米核进行保护。采用自主设计合成的双炔基连接臂,将炔基引入到磁性纳米粒子表面。通过荧光标记的方法对炔基修饰的磁性纳米粒子进行了表征。最后通过Click反应(Click reaction)将唾液酸碳苷化合物负载到纳米粒子表面。所合成的磁性纳米粒子将继续开展在磁共振成像、生物分离和肿瘤治疗等领域的应用研究工作。 第三章的内容为天然产物Pyrenolide D的全合成研究工作。Pyrenolide D是从大麦网斑病菌的次级代谢产物中分离出来的具有独特的螺环-γ-内酯结构的手性天然产物。它对肿瘤细胞HL-60表现出了良好的抑制活性(IC50 4μg/mL-1)。我们以D-木糖为手性起始原料,经过7步转化完成了Pyrenolide D的全合成,该合成路线是现有文献报道中最为简洁的。同时,针对Pyrenolide D分子中的螺环-γ-内酯结构,我们探索了新的合成策略,这对于具有类似结构化合物的合成研究有一定的指导作用。 第四章报道了活性天然产物Ribisin A的首次全合成研究。Ribisin A是从木藨子木层孔菌中分离出来的具有高含氧苯并呋喃结构的天然化合物。Ribisin A的生物活性研究表明,它能够显著的促进神经细胞PC12的生长。对于Ribisin A的合成,我们从易得的葡萄糖甲基苷出发,经过11步的转化,最终以21.6%的总收率首次完成了它的全合成研究。该合成路线涉及Ferrier碳环化反应、Johnson α-碘代反应、Suzuki 偶联反应和Wacker 氧化环化等关键反应,为具有相似结构(高含氧苯并呋喃结构)化合物的合成提供了一条简洁高效的参考合成路线。
英文摘要:       Carbohydrates are the most abundant biomolecules in nature and essential elements in a wide range of processes in living systems. Complex carbohydrate structures are involved in cell communication, immune responses, fertilization, apotosis, and infection. Carbohydrates are now receiving enormous attention and interest in the field of biological and medical research and the research of carbohydrate-based drugs also has been developed. In addition, carbohydrates are structurally polyhydroxy aldehydes and ketones, which make it possible carbohydrates involved in synthesis of chiral natural products as natural chiral templates with simplifying synthetic routes. This paper was divided into four chapters and included a review of glyconaoparticles research, Neu5Ac-C-galactopyranosyl-functionalized magnetic nanoparticles and total synthesis of two bioactive natural products. The first chapter reviewed the research progress of glyconanoparticles involving synthesis, characterization methodology and its application. Recently, nanomaterials and nanotechnology enjoyed the flourishing development, many encouraging result was achieved. Glyconanoparticles, as a class of nanomaterials, show a broad application prospects especially in the fields of medicine and biology with the development of new methods and technology. In the chapter 2, the research achievement about the synthesis of Neu5Ac-C-galactopyranosyl-functionalized magnetic nanoparticles was reported, including the design of synthetic route, the specific experimental steps and the characterization of related compounds and nanoparitcles. The C-glycosides was synthesized through the SmI2-mediated Barbier coupling reaction. The preparation of Fe3O4 related to a high-temperature hydrolysis and reduction of FeCl3 and the magnetic cores of the nanoparticles were wrapped with a silica-layer. The new linker, containing two alkynyl groups, was synthesized and then incorporated onto the nanoparticls surface by Si-O bonds. The presence of alkynyl groups on MNPs was confirmed by the fluorescent-labeled approach. Our results should be applicable to magnetic resonance imaging (MRI), biological separation and cancer treatment. The third chapter described the concise total synthesis of Pyrenolide D. It was isolated from the metabolites of Pyrenophora teres, containing tricyclic spiro-γ-lactone structure and exhibiting significant cytotoxic activity toward HL-60 cells at IC50 4 ?g/mL. The total synthesis was achieved in seven steps starting from D- xylose. To our knowledge, this synthetic route is shortest one reported in literatures. The current result provides an alternative method towards efficient preparation of bioactive Pyrenolide D and its analogs. The fourth chapter related to the first synthesis of Ribisin A. Ribisin A was isolated from the MeOH extract of the fruiting bodies of Phellinus gunus. The compound have highly oxygenated benzofuran skeleton and could promote neurite outgrowth in NGF-mediated PC12 cells.The first total synthesis of natural product Ribisin A has been achieved in 11 steps from commercially available methyl α-D-glucopyranoside with 21.6% overall yield. The key reactions involved Ferrier carbocyclization, Johnson iodination, Suzuki cross-coupling, and Wacker oxidative cyclization. This route of synthesis offers a concise and efficient synthetic route toward highly oxygenated benzofuran compounds.
内容类型: 学位论文
URI标识: http://ir.rcees.ac.cn/handle/311016/35177
Appears in Collections:环境化学与生态毒理学国家重点实验室_学位论文

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Recommended Citation:
张朝立. 负载唾液酸碳苷磁性纳米粒子及活性天然产物的合成研究[D]. 北京. 中国科学院研究生院. 2013.
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