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)--DFucpN2AcN4-(
14)--D-GalpA-(13)--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-) in collaboration with Dr. Dennis L. Kasper (Channing
Laboratory, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA). Unfortunately the trisaccharide was not active. / Chemistry
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1298 |
| Date | 11 1900 |
| Creators | Iynkkaran, Ithayavani |
| Contributors | David R. Bundle (Chemistry), Todd L. Lowary (Chemistry), Jed D. Harrison (Chemistry), John C. Vederas (Chemistry), Mavanur Suresh (Pharmacy), Bruce T. Grindley (Chemistry, Dalhousie University) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 1796261 bytes, application/pdf |
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