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Synthesis and Bioevaluation of Immunostimulant Glycolipids and Iminosugars

Author: ZhangZhenXing
Tutor: WangPeng
School: Nankai University
Course: Chemical Biology
Keywords: GLycolipid NKT cell KRN7000 iminosugar DNJ
CLC: O629.1
Type: PhD thesis
Year: 2012
Downloads: 5
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Abstract

As the α-linkage is very critical for the biological functions of theglycosphingolipids, many different methodologies have been developed to chemicallysynthesize this critical structure. However, these glycosylation reactions producedmostly a mixture of α/β isomers which were very difficult to separate. There isalways suspicion about the anomeric purity of synthetic galactosylceramide as it isdifficult to separate the α isomers from the β isomers, especially when they arepresent in trace amounts in the glycosylation reactions. Until now, there is nochemical glycosylation reaction in this area with100%α/β selectivity.Time-consuming separation procedures are required to separate the isomers from theabove synthetic methodologies, which lower the reaction efficiency and prevents themethods from being extended to large scale synthesis. To overcome the difficultiesand flaws of current synthetic methodologies, we chose to begin our synthesis ofα-galactosyl lipids from the naturally configured α-galactoside, raffinose. Byavoiding glycosylation reactions, a new and easily scaled synthesis of severalKRN7000analogues was developed via high yield reactions that could be easilyadapted to industrial scale synthesis.According the crystallographic data of the CD1d/α-GalCer complex, the ligand isstabilized with many hydrogen bonds. The first interaction involves the amino acidAsp151and two hydroxyl groups on D-Galactose (2-OH and3-OH). The Thr154actsas an H-bond donor with Asp151and as an H-bond acceptor with the amide group.The H-bond net could be influnced by changing the acidity of the amide donor, andthis should consequently influence the cytokine polarization produced by NKT cells.For the reasons above, thioacid amide KRN7000was synthesized as irritant to NKTcells. Primary assay have shown that it is activity against NKT cells.A novel and facile synthesis of a series of the biologically significant iminosugarderivatives including2-deoxynojirimycin, Miglustat and Miglitol is developed. Thesynthesis features a strategic double inversion mechanism for securing the desiredstereochemistry at C5position of such glucose-type carbohydrate mimetics,representing a practical and remarkable improvement on the previously reported method that suffers from the loss of the stereo-control during the reaction process.The absolute configuration of DNJ·HCl salt was also further unambiguouslyconfirmed by a single crystal X-γay analysis, from which it can be clearly seen thatC5configuration retains as the glucose type, namely,C5–C6bondorienting as anequatorial one, further corroborating our designed double-inversion strategy for theexquisite control of the desired stereochemistry during the synthesis.

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