| Summary: | 博士 === 國立清華大學 === 化學系 === 98 === Herpes simplex virus type 1 (HSV-1), a prevalent human pathogen causing chronic and recurrent lesions, belongs to the neurotropic subgroup of the herpes virus family. Cell surface heparan sulfate (HS) plays dual roles not only for assisting attachment of HSV-1 to the host cell, but also for inducing entry of the virus into the target cell. In 2008, Jian Liu identified that the specific 3-O-sulfonated octasaccharide 2, generated by enzymatic sulfonation of a heparin-degraded octasaccharide at the 3-O position of the second D-glucosamine unit from the reducing end, inhibited attachment and entry processes to the host cell during HSV-1 infection. However, the enzymatic synthesis may not be applicable in preparing the material in large scale. In addition, the exact HS structure was also not clearly defined. This dissertation is concerned with the development of methodologies for the synthesis of 3-O-sulfonated HS octasaccharide.
Chapter 1 begins with a description of the relationship about herpes virus and heparan sulfate on host cell surface, especially the role of 3-O-sulfonated HS in virus infection. Chapters 2 provides a brief introduction, and reviews the literature on the synthesis of heparin octasaccharide or longer sugar chain in recent years. The specific aims and the retro-synthetic plans of the new preparative approach are illustrated in Chapter 3.
Chapter 4 describes the stereoselective glycosylation of D-glucosamine. The roles of different protecting groups on the D-glucosamine donors are investigated, leading to the successful development of a powerful glycosyl donor for the formation of disaccharide 100 in high stereoselectivity and good yields. The conversion of the dual purpose disaccharide 100 into 63, 121, and 122 through functional group transformation or via regioselective deprotection is discussed in chapter 5.
Chapter 6 elaborates the construction of HP/HS oligosaccharide skeleton. The synthesis of the hexasaccharide 133 was carried out through a [2+2+2] reducing end to nonreducing end fashion and transformed into a glycosyl donor. Coupling of hexasaccharide donor with the 4-alcohol 60 followed by removal of the 2-naphthylmethyl (2-NAP) group and glycosidation with the L-idopyranosyl donor 59 generated the fully protected octasaccharide. After a series of functional group deprotection and transformations from fully protected octasaccharide, the final product 57 was acquired and subjected to bioassays, as specified in Chapter 7. In the future, interaction between 57 and HSV-1 glycoprotein gD, particularly, the complex structure at the molecular level, will be further studied to provide valuable information for the discovery of new anti-HSV-1 drugs.
The conclusion of this work is summarized in Chapter 8. Finally, Chapter 9 provides the detailed experimental section and the characterization of new compounds.
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