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Synthesis of Conformationally Restricted Oligosaccharides

Wilstermann, Michael LU (1997)
Abstract
Gangliosides are sialic acid-containing glycosphingolipids that often are present in increased amounts on tumor cells. Since the gangliosides are hydroxy-acids, they can form lactones. The lactones have been suspected to be more immunogenic than the open forms, but are in practise poor immunogens due to their ease of hydrolysis. This thesis describes the synthesis of the hydrolytically stable lactam analogs of GM2, GM3, and GM4 gangliosides, and derivatives related to them. Xylose and ceramide are intrinsic components of proteoglycans and glycolipids respectively. The proteoglycan biosynthetic pathway in human melanoma cells and Chinese hamster ovary cells has earlier been shown to transgress into the glycolipid pathway upon treatment of... (More)
Gangliosides are sialic acid-containing glycosphingolipids that often are present in increased amounts on tumor cells. Since the gangliosides are hydroxy-acids, they can form lactones. The lactones have been suspected to be more immunogenic than the open forms, but are in practise poor immunogens due to their ease of hydrolysis. This thesis describes the synthesis of the hydrolytically stable lactam analogs of GM2, GM3, and GM4 gangliosides, and derivatives related to them. Xylose and ceramide are intrinsic components of proteoglycans and glycolipids respectively. The proteoglycan biosynthetic pathway in human melanoma cells and Chinese hamster ovary cells has earlier been shown to transgress into the glycolipid pathway upon treatment of the cells with 4-methylumbelliferyl b-D-xylopyranoside. We have synthesized Xylb-, Galb1-4Xylb-, NeuAca2-3Galb1-4Xylb-2-(trimethylsilyl)ethyl and ceramide glycosides of potential use for investigations of the substrate specificity of glycosyl transferases in proteoglycan and glycolipid biosynthesis. Furthermore, the xylose containing GM3-lactone and -lactam analogs were synthesized. Galabiose is an integral part of a number of important glycolipids of the globo series. Galabiose is the minimum binding epitope for Streptococcus suis, uropathogenic E. coli, and verotoxin. The hydrogen bond between HO-6 and HO-2' in galabiose was emulated by a methylene bridge, thus introducing a conformational restriction. The synthesis of the methylene bridge prompted development of a novel reagent combination, NIS/TfOH/formaldehyde diphenylmercaptal. The conformationally restricted 2-(trimethylsilyl)ethyl galabioside was found to bind to S. suis, but less well than the parent compound. This was probably due to a slightly distorted conformation in the methylene bridged compound. As expected, the conformationally restricted galabiosides were not recognized by PapG (E. coli) or verotoxin, because of the need for intact HO-6 and HO-2'. (Less)
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author
opponent
  • Dr Boons, Gert-Jan, School of Chemistry, University of Birmingham, Edgbaston, England
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Streptococcus suis, E. coli, neoglycolipid, ganglioside-lactam, xylose, methylene acetal, sialic acid, Conformational Restriction, galabiose, Organic chemistry, Organisk kemi
pages
82 pages
publisher
Organic Chemistry, Lund University
defense location
Chemical Center, sal C
defense date
1997-04-04 13:15
external identifiers
  • Other:ISRN: LUTKDH/(TKOK-1042)/1-82/(1997)
ISBN
91-628-2407-4
language
English
LU publication?
yes
id
6cf592ae-88c2-4458-982b-dbe9782bcec4 (old id 29108)
date added to LUP
2007-06-14 11:59:46
date last changed
2016-09-19 08:45:13
@misc{6cf592ae-88c2-4458-982b-dbe9782bcec4,
  abstract     = {Gangliosides are sialic acid-containing glycosphingolipids that often are present in increased amounts on tumor cells. Since the gangliosides are hydroxy-acids, they can form lactones. The lactones have been suspected to be more immunogenic than the open forms, but are in practise poor immunogens due to their ease of hydrolysis. This thesis describes the synthesis of the hydrolytically stable lactam analogs of GM2, GM3, and GM4 gangliosides, and derivatives related to them. Xylose and ceramide are intrinsic components of proteoglycans and glycolipids respectively. The proteoglycan biosynthetic pathway in human melanoma cells and Chinese hamster ovary cells has earlier been shown to transgress into the glycolipid pathway upon treatment of the cells with 4-methylumbelliferyl b-D-xylopyranoside. We have synthesized Xylb-, Galb1-4Xylb-, NeuAca2-3Galb1-4Xylb-2-(trimethylsilyl)ethyl and ceramide glycosides of potential use for investigations of the substrate specificity of glycosyl transferases in proteoglycan and glycolipid biosynthesis. Furthermore, the xylose containing GM3-lactone and -lactam analogs were synthesized. Galabiose is an integral part of a number of important glycolipids of the globo series. Galabiose is the minimum binding epitope for Streptococcus suis, uropathogenic E. coli, and verotoxin. The hydrogen bond between HO-6 and HO-2' in galabiose was emulated by a methylene bridge, thus introducing a conformational restriction. The synthesis of the methylene bridge prompted development of a novel reagent combination, NIS/TfOH/formaldehyde diphenylmercaptal. The conformationally restricted 2-(trimethylsilyl)ethyl galabioside was found to bind to S. suis, but less well than the parent compound. This was probably due to a slightly distorted conformation in the methylene bridged compound. As expected, the conformationally restricted galabiosides were not recognized by PapG (E. coli) or verotoxin, because of the need for intact HO-6 and HO-2'.},
  author       = {Wilstermann, Michael},
  isbn         = {91-628-2407-4},
  keyword      = {Streptococcus suis,E. coli,neoglycolipid,ganglioside-lactam,xylose,methylene acetal,sialic acid,Conformational Restriction,galabiose,Organic chemistry,Organisk kemi},
  language     = {eng},
  pages        = {82},
  publisher    = {ARRAY(0xae292d0)},
  title        = {Synthesis of Conformationally Restricted Oligosaccharides},
  year         = {1997},
}