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Synthesis of the repeating unit of Streptococcus pneumoniae (Sp1) zwitterionic polysaccharide Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Iynkkaran, Ithayavani
Supervisor and department
David R. Bundle (Chemistry)
Examining committee member and department
Mavanur Suresh (Pharmacy)
John C. Vederas (Chemistry)
Bruce T. Grindley (Chemistry, Dalhousie University)
Jed D. Harrison (Chemistry)
Todd L. Lowary (Chemistry)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
According to the traditional paradigm, carbohydrates are considered to be poorly immunogenic, T-cell independent antigens. Pure polysaccharides induce specific IgM responses, with minimal class switch to IgG. However, a series of recent investigations has found that a class of zwitterionic polysaccharides (ZPSs)induces a variety of T-cell specific responses such as cell proliferation,cytokine secretion, and regulation of antibody production. The two most studied among this family of molecules is capsular polysaccharide (PS) A1 from the Bacteroides fragilis and the type 1 Streptococcus pneumoniae polysaccharide capsule (Sp1). Active ZPSs share a common structural motif; a high density of positively charged amino and negatively charged carboxyl or phosphate groups. These features are essential for the activity of ZPSs. Since the biological repeating unit of the polysaccharides is not known and biological activity will most likely depend upon a precise sequence, synthesis of the repeating unit of these capsular polysaccharides was undertaken. The goal of this work is to synthesize the repeating unit [→3)-α-DFucpN2AcN4-( 1→4)-α-D-GalpA-(1→3)-α-D-GalpA-(1→] of the type 1 capsular polysaccharide (Sp1) found in S. pneumoniae. 2-Acetamido-4-amino-2,4,6- trideoxy-D-galactopyranose is one of the three monosaccharides of the repeating unit of the Sp1 of Streptococcus pneumoniae. This rare amino sugar is also present in a number of bacterial polysaccharides such as Bacteroids fragilis, Streptococcus mitis and Shigella sonnei. We have developed a novel method to synthesize the orthogonally protected 2-acetamido-4-amino-2,4,6-trideoxy-Dgalactopyranose on a gram scale with high yield starting from readily available Dglucal. The crucial elements of this approach are the introduction of a 4 amino function via intramolecular cyclization of a 3-O-N-benzylcarbamate. The resulting N-benzyloxazolidinone derivative after conversion to the corresponding glycosyl trichloroacetimidate was shown to be an effective glycosyl donor. The assembly of the trisaccharide was successfully carried out from the appropriate galactopyranosides selectively protected at O-6 to permit oxidation to uronic acid derivatives after successful assembly of the target trisaccharide. The trisaccharide was tested for its ability to stimulate interleukin 10 (IL-10) and Interferon-gamma (IFN-γ) in collaboration with Dr. Dennis L. Kasper (Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA). Unfortunately the trisaccharide was not active.
License granted by Ithayavani Iynkkaran ( on 2010-08-19T19:35:52Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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