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

  • Author / Creator
    Iynkkaran, Ithayavani
  • 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.

  • Subjects / Keywords
  • Graduation date
    2010-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3KT4X
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • David R. Bundle (Chemistry)
  • Examining committee members and their departments
    • Todd L. Lowary (Chemistry)
    • Bruce T. Grindley (Chemistry, Dalhousie University)
    • Mavanur Suresh (Pharmacy)
    • Jed D. Harrison (Chemistry)
    • John C. Vederas (Chemistry)