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Synthetic Studies Of The Oligosaccharide Analogs Of The Cell Surface Polysaccharides Of Streptococcus Pneumoniae Serotype 23F And Clostridium Difficile

Posted on:2018-12-17Degree:DoctorType:Dissertation
Country:ChinaCandidate:K YuFull Text:PDF
GTID:1314330512489868Subject:Organic Chemistry
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Carbohydrate,the most abundant organic molecule in nature,distributes widely in animals,plants,and microorganisms.It usually exists in the form of glycolconjugates,such as glycoproteins,glycolipids and so on,and is known as one of the three basic substances of lives,together with protein and nucleic acid.Carbohydrate is required to sustain life by participating in varieous life activities,such as biosynthesis,recognition,cell adhesion and so on.Carbohydrate is also closely associated with various diseases,such as cancer development,viral and bacterial infections,and so on.So far,clinical treatments of bacterial infections rely on mainly antibacterial drugs,especially antibiotics.With the long-term utilization and abuse of antibiotics,it has been discovered that many bacterial pathogens start to exhibit strong resistance to multiple antibiotics.Therefore,the development of new therapies,including new vaccines,against multidrug-resistant bacterial pathogens is an urgent and hot topic.It has been well established that the surface of all cells,including bacterial cells,is covered by a layer of carbohydrate,which is know as glycocalyx.Carbohydrate,as an important composition of bacterial cell surface structure,plays an important role in bacterial survival,growth,virulence,infection,evasion of the host immune system,etc.Moreover,bacterial glycocalyx is not only directly exposed on the cell surface but also is relatively conserved and has some imunogenicity.Thus,it becomes the ideal souce of antigens for vaccine development.However,the imunogenicity of carbohydrates is usually weak and they are T cell-independent.Thus,they can only induce weak B cell responses that lack immune memory effects.All these problems have hindered the development of effective vaccines based on carbohydrate antigens.Fortunately,studies in recent decades have found that the conjugates of carbohydrates,such as bacterial polysaccharides,and immunogenic proteins can possess improved immunity and stimulate T cell-dependent immune responses.Thusfar,glycoconjugate vaccines derived from bacterial cell surface polysaccharides have been widely used in clinic.Currently,the polysaccharides used in the preparation of glycolconjugate vaccines are usually extracted from bacterial cells and/or cell cultures.The structural heterogeneity of natural polysaccharides and the risk of remaining impurities have caused difficulties in the study and evaluation of structure-activity relationships and in quality control of synthetic glycoconjugate vaccines.Therefore,chemical synthesis has become an important approach to obtain carbohydrate antigens with well-defined structures.In this regard,we have designed and synthesized oligosaccharide fragments and analogs of Streptococcus pneumoniae serotype 23F capsular polysaccharide(CPS)and lipteichoic acid of Clostridium difficile.This disertation includes three major parts:Chapter 1 provides a brief introduction to the current status of epidemiologic study on diagnostic and therapeutic methods and vaccine development for S.pneumoniae serotype 23F and C.difficile.Chemical structures of S.pneumoniae serotype 23F CPS and C.difficile cell surface polysaccharides and synthetic studies on their oligosaccharide fragments,have also been reviewed.Chapter 2 describes the chemical synthesis of 3-aminopropyl glycoside of the biological repeating unit of S.pneumoniae serotype 23F CPS.The synthetic target SP-2 contained a tetrasaccharide backbone with a phosphoglycerol branch.The oligosaccharide backbone SP-5 was assembled via sequential glycosylation of glycosyl acceptor SP-6 with monosaccharide glycosyl donors SP-7,SP-8,and SP-9,respectively.In the synthesis of SP-5,the challenging(3-rhamnosyl linkage in its structure was achieved stereospecifically through naphthylmethyl-assisted intramolecular aglycon delivery(IAD).The remaining 1,2-trans glycosylation reactions were executed in excellent yields and stereoselectivity based on neighboring group participation effect.The phosphoglycerol branch was installed by the phosphoramidite method with benzylidene-protected glycerol 2-phosphoramidite SP-4 as the substrate to give SP-3 as the single isomer.Finally,benzyl ether/benzylidene acetal deprotection with hydrogenolytic reduction of SP-3 completed the synthesis of the target molecule SP-2.The synthetic target contained a free amino group at its reducing end,facilitating its conjugation with other molecules for various biological studies and applications.Chapter 3 describes the chemical synthesis of oligomer analogs of lipteichoic acid of C.difficile.Two structurally defined and functionalized analogs CD-1 and CD-2 of lipteichoic acid(LTA)from C.difficile were efficiently synthesized via a convergent[2+3]or[2+2+3]strategy,respectively.Both syntheses used D-glucose as the starting material.The a-linkages of N-acetylglucoamine residues in the key disaccharide repeating units CD-5 and CD-6 were realized using azidosugar trichloroacetimidates as glycosyl donors.In the synthesis of CD-7,the β-glucosyl linkages were achieved efficiently and stereoselectivly based on neighboring group participation effects.The phosphodiester bridges between different oligosaccharide moieties were constructed by the phosphorylation method using H-phosphonates.Again,the synthetic targets contained a free amino group at the core triaccharide reducing end,which would facilitate their conjugation with other molecules for various biological studies and applications.
Keywords/Search Tags:Streptococcus pneumoniae serotype 23F, Clostridium difficile, Capsular polysaccharide, Lipteichoic acid(LTA), Chemical synthesis
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