基于糖共轭物的化学生物学研究

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作者：刘博 论文级别：博士 学科专业名称：药物化学 中文关键词：O-糖肽 ; 固相糖基化 ; F-SPE ; “安全拉手”连接桥 ; 链球菌 ; 选择性抗菌 ; 糖脂天然产物 ; 菌膜通透性 ; 分子内糖苷传递反应 英文关键词：O-glycopeptides ; solid-phase glycosylation ; F-SPE ; "safty-catch" linker ; streptococcus ; Morinda citrifolia ; selectively anti-bacteria agent ; glycolipid ; natural 英文关键词：product ; targeting the membrane permeability ; IAD reaction 学位年度：2014 导师：刘刚 学科代码：100701 学位授予单位：北京协和医学院 论文提交日期：2014-05-01

摘要

糖类结构在人体生命活动(细胞的信号识别进程、免疫系统功能、维持细胞基本形态及功能等)以及多种重大疾病的病理学(肿瘤、心血管疾病、感染性疾病等)进程中都发挥着至关重要的作用。糖共轭物(糖肽、糖脂)是糖类结构发挥功能的主要存在形式,同时由于糖共轭物结构所蕴含的巨大的多样性,使得其相关的化学生物学研究越来越受到人们的关注。然而十分有限的物质来源却限制对糖共轭物的进一步深入研究。因此,探索能够快速合成以及分离糖共轭物的方法以及发现并探讨基于新颖结构以及新的生物学作用机制的糖共轭物的构效关系研究就具有非常重要的意义。为此,本论文主要研究两方面的内容：1)创建利用氟相化学辅助固相合成〇-连接糖肽的新方法；2)具有链球菌菌属特异性抗菌活性的全新糖脂天然产物TTSG类似物的设计与合成。
     一)氟相化学辅助的固相O-连接糖肽的合成
     由于糖肽结构中寡糖片段的微观不均一性以及生物合成途径中糖基化位点的不可控性,使得通过生化分离手段难以得到结构确定的糖肽,发展一种能够快速合成以及分离得到具有结构特定的糖肽的合成方法以期望在后续研究中能够构建多样化的糖肽库,从而满足基于糖肽结构的药物发现以及全新糖肽疫苗的设计与发展的需求就成为了糖肽研究领域的一个热点。
     目前糖肽合成一种较为普遍采用的策略就是利用预先制备的连有寡糖片段的氨基酸作为一个构建单元,借助于固相多肽合成(SPPS)的逐步合成方法制备目标的糖肽结构并利用色谱方式进行分离纯化。这种方法操作繁琐,合成以及分离效率较低,同时合成结果较大的多变性也限制了其应用。
     因此,本论文探索结合固相糖基化方法、氟相化学中氟标记的糖基供体策略和氟的固相萃取技术(F-SPE)以及固相合成方法学等多种手段设计了一种新颖高效的固相合成以及分离O-连接糖肽的策略。在该策略中,以连有芳基酰肼“安全拉手”连接桥的亲水性的TentaGel树脂为固相载体,通过固相多肽合成(SPPS)方法延伸糖肽分子的多肽链,经过选择性脱保护,游离出糖基片段连接位点,利用固相糖基化的方式逐步引入糖基片段,固相糖基化过程中,经过过滤洗涤等固相合成中的简单操作,就可直接进行下一步反应。合成操作结束后,芳基酰肼“安全拉手”连接桥的应用使得该策略可以在温和条件下裂解目标的糖肽分子,避免了酸敏以及碱敏连接桥分子对糖肽结构的破坏。再通过氟相化学的固相萃取技术(F-SPE)可以快速简便的分离得到纯的目标糖肽分子。
     本课题通过结合固相合成以及氟相化学的优势,借助于我们课题组发展的氟标记的糖基供体策略以及首次被应用于固相合成O-连接糖肽方法中的芳基酰肼“安全拉手”连接桥,创建了一种快速高效的合成O-连接糖肽的方法。该方法操作简便快速,对于实现糖肽的自动化合成起到巨大的推动作用。
     二)具有链球菌菌属特异性杀菌活性的全新糖脂天然产物TTSG类似物的设计、合成、活性评价以及初步的作用机制研究。
     链球菌是一类包含多种重要致病菌的菌属,由其感染所导致的疾病(鼻窦炎、脑膜炎、中耳炎、细菌性肺炎、心内膜炎等)对人类健康造成了极大的危害。目前临床的首选治疗药物通常是青霉素,然而近年来伴随着青霉素耐药的链球菌菌株的出现以及不断传播,使得单纯依靠青霉素进行治疗链球菌感染所引起的疾病已经越来越困难,而联合其他广谱抗生素又会很大程度的破坏人体的菌群平衡,从而对人类健康造成更大的威胁。因此发展一种既能够对抗耐药菌同时又符合个性化治疗理念的具有针对性对抗链球菌活性的新型抗生素,在尽可能不破坏人体菌群平衡的前提下快速的杀灭致病链球菌则是链球菌感染性疾病治疗的最佳选择。
     本课题以首次发现的一种从夏威夷诺丽果果实中提取出来的全新的糖脂类天然产物TTSG的结构为基础,通过逆合成分析,巧妙的设计了该三糖糖脂类结构化合物的合成路线,通过使用包括分子内糖苷传递反应构建海藻糖糖苷键以及高立体选择性构建p-甘露糖苷键等方法首次完成了对该类新颖结构的全合成。除此之外本课题的其他成果包括：
     1)扩展了利用分子内糖苷传递反应构建1,1-α,α-海藻糖苷键以及通过原位活化生成氧蓊离子的方法高立体选择性的构建p-甘露糖苷键等反应的应用范围并且验证了其对于糖脂类结构的适用性。
     2)通过理性的药物分子设计,从不同的角度设计了该天然产物的多个结构类似物。并且通过多条优化的合成路线制备得到了该天然产物结构为基础的20个的结构类似物。
     3)通过活性评价从中发现了多个对于链球菌菌属具有高选择性快速杀菌作用的活性的化合物。
     4)通过检测对多种临床耐药菌的链球菌菌株的杀菌作用,证明了活性化合物54对于临床耐药菌株的高敏感性。并通过化合物对人体红细胞的溶血实验确证了化合物的安全性。
     5)以活性化合物54为研究对象利用DIS-C3-5染色实验进行初步的作用机制研究,证实了化合物54是通过选择性破坏链球菌菌膜通透性起到杀菌作用的活性化合物。并通过原生质体杀菌实验初步验证了化合物54对于菌属的选择性可能是由于该类活性化合物对于不同细菌菌属细胞壁的通透性的差别产生的。
Carbohydrates play a vital role in many physiological processes including cell adhesion, cell differentiation, infected agent that make us ill, as well as in major diseases such as cancer, cardiovascular disease and inflammatory diseases. Glycoconjugate(glycopeptides/glycolipid) are the major bioactive form of oligosaccharide. Scientists have paid more and more attention on glycoconjugate since the huge diversity in it. But the further understanding the functions of glycoproteins and glycopeptides and analyzing their structure-activity relationships (SARs) is restricted by their limited supplemental resources. Therefore exploring rapid and efficiently artificial synthetic approaches to access the target glycopeptides, and finding the novel bioactive glycocongate for vaccine and drug discovery is very important. This thesis pursued the studies on two aspects:(1) A new approach for the synthesis of O-glycopeptides through a combination of solid-phase glycosylation and fluorous tagging (2) Reasonable design and total synthesis of analogues of TTSG from Morinda citrifolia, which act as highly selective antibiotic agent and target the membrane of bacteria.
     1) A new approach for the synthesis of O-glycopeptides through a combination of solid-phase glycosylation and fluorous tagging
     As we all know, it is difficult to separate glycopeptides from natural glycoforms, by means of microheterogeneity at carbohydrate portions and uncontrollable glycosylation in the biosynthetic approach. To overcome these obstacles, there is a need for rapid and efficiently artificial synthetic approaches to access the target glycopeptides, especially methods for preparing pure and structurally well-defined glycopeptides libraries for vaccine and drug discovery.
     Using preformed glycosylated amino acids or oligosaccharides as building blocks during solid-phase synthesis of glycopeptide and purified by the HPLC is currently the most popular method for synthesizing glycopeptides. However, it suffers from cumbersome operation, low efficiency and an apparently variable synthetic outcome from one target product to another.
     Herein, we report the first attempt of solid-phase synthesis of O-linked glycopeptides through the combination of a solid-phase hybrid glycopeptidation procedure and fluorous tagging strategy in this thesis. In this strategy, a TentaGel resin with an aryl hydrazine "safety-catch" linker was selected as the solid phase support, after constructing the peptides portion by the SPPS strategy, the saccharine motif was introduced step by step with the help of the solid-phase glycosylation. the stable aryl hydrazine linker under reactions conditions eliminates the risk of destruction the structure of the desired glycopeptide because of its acidic and/or basic liability to the glycomoiety and side-protection groups of peptides. Finally F-SPE protocol allowed us to purify the target product simply.
     This project report a new and efficient hybrid strategy to synthesize and purify O-glycopeptides was developed via a combination of the advantages of solid-phase glycosylation strategy with the superiority of fluorous chemistry. This approach not only introduces a fluorous-tagged glycosyl donor and aryl hydrazine safety-catch linker into the solid-phase synthesis of O-linked glycopeptides for the first time, but also avoids generation of extra costs with the help of solid-phase glycosylation and F-SPE chemical recycling. This strategy will be a significant advance in realizing automated O-linked glycopeptide synthesis for nonspecialists.
     2) Reasonable design and total synthesis of analogues of TTSG from Morinda citrifolia, which act as highly selective antibiotic agent and target the membrane of bacteria.
     Streptococcus is a kind of Gram-positive bacteria including many pathogenic bacteria which could induce nasosinusitis, bacterial meningitis, otitis media, bacterial pneumonia, endocarditis et. al., it is a huge threat to the health of human being. The first medical choice in clinic is the penicillins'antibiotics. However, the emerging of penicillin resistance streptococcus make it difficult to cure the disease caused by the streptococcus. But combined the broad-spectrum antibiotic could destroy the normal balance of bacteria in human body, which may be even more harmful for the public health. Develop an antibiotic agent which not only have specific killing effect to the streptococcus, but also is sensitive to the clinical drug resistance streptococcus for the harmless of the normal balance of bacteria in human body would be the optimal choice.
     This project syntheses19analogues of a novel glycolipid natural product which was extracted from the fruit of Morinda citrifolia with a wisely designed route, including the IAD reaction for preparing the1,1-α,α trehaloside and the highly stereoselectively constructing the P-mannoside. Besides that, there are still some other valuable results in this part of the thesis:
     1) Largely expanded the application of IAD reaction to establish the trehaloside and the feasibility of using the oxonium which generated in situ to highly stereoselectively construct theβ-mannoside in the synthesis of glycolipid motif.
     2) Rational designed a few analogues of TTSG, and prepare19compounds by means of optimized routes.
     3) Discovering some rapidly and specifically anti-streptococcus bioactive agents.
     4) Identify the sensitivity of our synthetic analogue compound54to the multidrug-resistance streptococcus.
     5) Using the hemolysis assay to identify the safety of our bioactive compounds.
     6) Preliminary demonstrated the mechanism of action is targeting the cell membrane of the bacteria by taking the active compound54as an example. And identify that the reason of the genus selectivity of the killing effect may be the different permeability between the various bacteria according to the protoplast assay.

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