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Synthesis of a C-glycoside analogue of β-D-galactosyl hydroxynorvaline and its use in immunological studies
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2000 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 1, no 4, 272-280 p.Article in journal (Refereed) Published
Abstract [en]

A C-linked isostere of β-d-galactosylated hydroxynorvaline has been prepared in eight steps from per-O-benzylated galactopyranolactone. Addition of a homoallylic Grignard reagent to the lactone, reduction of the resulting hemiacetal with triethylsilane, and a Wittig reaction with Garner's aldehyde were key steps in this synthesis. The C-linked building block was then incorporated at position 264 into the fragment CII(256–270) from type II collagen by solid-phase synthesis using a combination of the tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategies. Deprotection of the benzylated C-linked galactosyl moiety was achieved simultaneously with cleavage of the glycopeptide from the solid phase by using triethylsilyl trifluoromethanesulfonate in TFA. Helper T-cell hybridomas obtained in a mouse model for rheumatoid arthritis responded to the C-linked glycopeptide when presented by class II MHC molecules. However, 10- to 20-fold higher concentrations were required as compared to when O-linked β-d-galactosylated hydroxynorvaline or hydroxylysine (Hyl) were present at position 264 of CII(256–270). Thus, replacement of a single oxygen atom by a methylene group in the carbohydrate moiety of a glycopeptide antigen had a substantial influence on the T-cell response. This reveals that T cells are able to recognize the carbohydrate moiety of glycopeptide antigens with high specificity. Finally, the results suggest that structural modifications of β-d-Gal-Hyl264in CII(256–270) may give altered peptide ligands that can be used for induction of tolerance in autoimmune rheumatoid arthritis.

Place, publisher, year, edition, pages
John Wiley & Sons, 2000. Vol. 1, no 4, 272-280 p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-4779DOI: 10.1002/1439-7633(20001117)1:4<272::AID-CBIC272>3.0.CO;2-WOAI: oai:DiVA.org:umu-4779DiVA: diva2:144017
Available from: 2005-11-03 Created: 2005-11-03 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Asymmetric Synthesis of C-Glycosylated Amino Acids: Incorporation in Collagen Glycopeptides and Evaluation in a Model for Rheumatoid Arthritis
Open this publication in new window or tab >>Asymmetric Synthesis of C-Glycosylated Amino Acids: Incorporation in Collagen Glycopeptides and Evaluation in a Model for Rheumatoid Arthritis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes stereoselective syntheses of four amino acids, three of which are C-glycosidic analogues of glycosylated amino acids. The overall goal of the project was to probe the interactions between MHC molecules, glycopeptide antigens and T cell receptors, that are essential for development of collagen induced arthritis. Collagen induced arthritis is a frequently used mouse model for rheumatoid arthritis, an autoimmune disease that attacks joint cartilage and leads to a painful and eventually crippling condition.

The thesis is based on four studies. The first study describes the synthesis of hydroxylysine, an amino acid that is found in collagen and is an important constituent of the glycopeptide proposed as an antigen in collagen induced arthritis. During the synthesis of hydroxylysine some new insight into the mechanism of the reductive opening of p-methoxybenzylidene acetals was obtained.

The remaining three studies deals with the synthesis of C-glycosidic analogues of glycosylated amino acids, hydroxy norvaline, threonine and hydroxylysine.The synthesis of each amino acid required control of several stereogenic centra and utilizes a variety of approaches such as use of stereoselective reactions, chiral auxilaries, chiral templates and asymmetric catalysis.

The C-glycosidic analogues of galactosylated hydroxynorvaline and hydroxylysine were incorporated in glycopeptides from type II collagen and evaluated in T cell response assays. It was found that the T cells were stimulated by the C-glycopeptides, but that higher concentrations were required than for the native O-glycopeptide

Place, publisher, year, edition, pages
Umeå: Kemi, 2005. 93 p.
Keyword
Total synthesis, stereoselective synthesis, chiral glycine templates, Evan’s alkylation, asymmetric hydrogenation, alpha-amino acid synthesis, C-glycoside, rheumatoid arthritis, MHC, T cell
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-623 (URN)91-7305-975-7 (ISBN)
Public defence
2005-11-25, 13:00
Supervisors
Available from: 2005-11-03 Created: 2005-11-03 Last updated: 2012-05-23Bibliographically approved

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