Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/90561
標題: Part 1: Formal Synthesis of a Disaccharide Repeating Unit (IdoA-GlcN) of Heparin and Heparan Sulfate Part 2: Concise Synthesis of alpha-Galactosyl Ceramide (KRN7000) and Natural Cerebroside with Their Analogues
第一部分:進行肝素與硫酸乙醯肝素的雙醣重複單元(IdoA-GlcN)的合成 第二部分:alpha-galactosyl ceramide、natural cerebroside與它們的衍生物的簡潔合成
作者: 迪抽土
Ratnnadeep Sawant
關鍵字: KRN7000
Heparin
Heparan Sulfate
Glycosylation
肝素
硫酸乙醯肝素
醣苷化反應
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摘要: In the first chapter of thesis, investigations into the synthesis of a disaccharide repeating unit (IdoA-GlcN) of haparin and heparan sulfate are described in full detail. The synthesis was accomplished starting from a diacetone -D-glucose to functional group transformations lead to the formation of L-idurunate donor. This L-idurunate donor was further selectively coupled with glucosyl acceptor to form corresponding key disaccharide repeating unit (IdoA-GlcN) of heparin sulfate in good overall yield. In the first section of second chapter of thesis, a series of KRN7000 derivatives were designed and synthesized with a view to testing their immune stimulant activity. However, following the previously developed five step method for the synthesis of KRN7000, we have synthesized 6-OH modified and hydroxylated analogues having additional hydroxyl group in the phytosphingosine chain with varying stereochemistry. Careful selection of glucose, galactose, mannose, and talose hexopyranoses allowed us to control the stereochemistry of a few hydroxyl groups in the sphingosine chain to furnish some interesting hydroxylated KRN7000 analogues. During the Wittig reaction of the pyrano-type reducing sugars undergoes an unexpected formation of dienes through the elimination of a benzyloxy group in the presence of t-BuOK. LiHMDS is used rather than t-BuOK to prevent alcohol elimination in the same sugar derivatives. This unusual function of t-BuOK showed that a unique 4-deoxy-5-hydroxy analogue of KRN7000 was formed exclusively. Ceramide NH-modified KRN7000 analogues have been synthesized from pyrano-reducing sugars with D-galactosyl iodide through direct and simple synthetic route. A methyl group has been installed at the amide and O-6 group of KRN7000. Of the derivatives synthesized have immune stimulant efficacy comparable with KRN7000. The results suggest that the nature of the phytosphingosine core plays a significant role in the selective secretion of Th1 or Th2 cytokines which ultimately acts as immune stimulant with KRN7000. In the second section of second chapter of thesis, we are on the way to finalize the synthesis of natural cerebroside using the commercially available compounds. The tetrahydroxy-LCB acceptor was prepared according to our previously published route and lipid chain was synthesized from acetonide protected D-glyceraldehyde. The cleavage of amide bond during the final deprotection was overcome by changing the deprotection style before finalizing the synthesis of target compound. This newly developed route will access to the other analogues of natural cerebroside which may find a good biological activity.
URI: http://hdl.handle.net/11455/90561
文章公開時間: 2018-06-15
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