【作者】 孙静；

【导师】 俞永平；

【作者基本信息】 浙江大学 ， 药物化学， 2007， 硕士

【摘要】 作为肽类化合物中最有特点的一类,环肽以激素、抗生素、离子载体系统、抗真菌素、癌抑制剂以及毒素的形式展现出丰富多样的生物活性。到20世纪中期,已经分离得到几个有代表性的环肽,阐明了它们的结构,并完成了对它们全合成的研究。在过去的40年间,从植物、真菌、细菌及海洋生物中分离得到的特殊结构的环肽数目迅速增加。由于环肽活性部分的柔性和构象受到限制,使之适合与受体相互作用,基于这些研究可获得关于受体-配体相互作用在结构信息方面的重要结论。环肽可作为蛋白质识别的模型,还可用于模拟β折叠、β转角或γ转角等。因为天然的高活性肽只以微量存在,而且分离及其困难。大多数情况下,只能由合成的方法获得足量的肽用于生物学研究。因此,全合成是获得结构多样性及优化生物学性质的最佳方法。随着硫酯法等一系列新的环肽合成方法的出现,以及一些新的缩合剂在反应中的使用,环肽合成有了很大的发展,现已发展了许多环肽的合成方法与合成策略,各种方法均有其特点及优缺点。本文利用氨烷基聚硅氧烷类作为固相合成载体,以5种氨基酸作为合成羟基多肽化合物库的原料,包括丙氨酸、苯丙氨酸、亮氨酸、天冬酰胺、脯氨酸,合成了环肽中间体羟基二肽、羟基三肽、羟基四肽化合物,通过环肽中间体羟基二肽类化合物,我们还合成了环肽。本方法的主要优点是成本低,操作简便,采用适当的切割条件分解固相载体为可挥发性的物质、连接剂和产物,真空干燥后直接得到产物,避免了萃取、分离、蒸发溶剂等步骤,非常适合平行合成和自动化合成化合物组合库以供活性筛选。随着人类基因组、蛋白质组研究的进行,以及高通量筛选技术的发展,以环肽合成技术为基础的环肽组合库研究在寻找蛋白质作用受点、药物作用靶点的三维构效关系的工作中将扮演一个重要的角色。寻找效率更高的环肽合成方法以及寻找更利于环肽合成的新树脂、新缩合剂将是一项具有理论和实际意义的工作。更多还原

【Abstract】 Cyclic peptides form a particular class of compounds with multiple and varied biological functions. These cyclic peptides act as potent antimicrobial, cytotoxic, antineoplastic, and antiviral agents of great therapeutic value. Cyclic peptides, in particular, attracted our attention as designer targets because of their demonstrated potential as antibiotics, regulators of membrane ion transport, and templates for protein design. During middle of the 20^th centuries, some scientists had separated a few kinds of cyclic peptides and completed total synthesis of these cyclic peptides. More cyclic peptides were found during the past 40 years. The conformational constraints of cyclic peptides have allowed them to serve as useful and predictable models of various protein structural motifs, includingβ-foldingβ-turn andγ-turn. They can also provide the elements required to delineate ligand-receptor and enzyme substrate/inhibitor interactions for a multitude of processes.Since it is difficult to get natural cyclic peptides by seperation, we have to use total synthesis in order to attain more cyclopeptides. With the development of new method and efficient coupling reagents, the synthesis of cyclopeptides has great changed. There are several ways to synthesize cyclic peptides; all of them have advantages and disadvantages.We use functional silica gel as volatilizable support and linker and react with several amino acids. Finally we get hydroxide peptides and cyclic peptides. Our method is exemplified by the solid-phase synthesis on "volatilizable" solid supports and linkers that can be completely removed by their ultimate decomposition and complete "volatilization" during the final cleavage step of the synthetic process. This approach eliminates the final extraction step and yields solely the desired synthetic product（s） in the reaction vessel. This method is suitable for the parellel synthesis and automatic synthesis of compound library used for screening.With the development of human genome, proteome and high throughout screening system, cyclic peptides play a vital role in study and mimicry of protein folding. We should try to find a more efficient method, resin and coupling reagent to synthesize cyclic peptides.更多还原