Design and syntheses of multivalent glycoconjugates containing sialic acid.
Creators: name: Gan, Zhonghong.
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 2000
Subjects: subject: Chemistry, Organic.

description: The importance of cell surface carbohydrates in biological processes has led to remarkable progress in carbohydrate synthesis and glycobiology. However, efficient protocols for building oligosaccharides from monosaccharide components are still the major challenges in the field of carbohydrate synthesis. On the other hand, individual carbohydrate-protein interactions are characterized by low affinities. This drawback can be overcome by using the "multivalent or cluster effect". Therefore, the chemical synthesis of oligosaccharides and multivalent glycoconjugates is presented herein. A very simple and efficient synthetic route towards N-acetyllactosamine derivatives was developed. This strategy has used "lightly protected" acceptors, 6-O-tert-butyldiphenylsilyl protected N-acetylglucosamine derivatives, to reduce tedious multiple protection and deprotection steps. Most importantly, these 6-O-tert-butyldiphenylsilyl protected N-acetylglucosamine acceptors allow the regiospecific introduction of a galactosyl moiety. In addition, this method constitutes a highly practical synthesis of Lewis X trisaccharide. The "active-latent" glycosylation strategy made it possible to manipulate the reactivity of both glycosyl donors and acceptors by means of changing the electron density of the aryl substituents at the anomeric center. This strategy provides a facile approach toward the synthesis of complex oligosaccharides such as Lewis X pentasaccharide in a highly convergent manner. The facile regio- and alpha-stereoselective glycosidation of Neu5Ac with several glycosyl acceptors was achieved using a thiophilic promoter (NIS/TfOH) in acetonitrile under kinetically controlled conditions. Under such conditions, the desired sialyl-alpha-(2→3)- and sialyl-alpha-(2→6)-sugar derivatives were obtained in good yields. The syntheses of sialyl alpha-(2→6) thioglycosides were also achieved in situ using diethylamine in chemoselective de-S-acetylation of thioacetate sialic acid derivative. These sialoside derivatives with their azido or p-nitrothiophenyl aglycone can be simply transformed into various neoglycoconjugates using well-established strategy. Glycoclusters with various valencies were synthesized using transition metal-catalyzed reactions. Grubbs' ruthenium benzylidene catalyst had been successfully applied in olefin metathesis reactions from alkenyl sialic acid derivatives. The reactions afforded divalent sialoside derivatives in reasonable yields under mild reaction conditions. Using copper (I)-catalyzed Glaser reaction and palladium-catalyzed Sonogashira reaction, divalent 'rod-like' glycoclusters; were prepared from terminal alkynes such as 2-propynyl thioglycosides in excellent yields. Such strategies also allowed 2-propynyl O-and S-sialic acid derivatives to form dimers, trimers and tetramers, respectively. Divalent sialosides scaffolded on p-tert-butylcalix[4]arene were prepared using an isothiocyanate conjugation strategy. Following the same strategy, a GM3 isothiocyanate derivative was coupled with multivalent amines based on gamma-resorcylic acid- or gallic acid-cores to give multivalent GM3 ligands in good yields. This strategy was extended to synthesize starburstRTM PAMAM-based glycodendrimers. PAMAM cores with generation G0 to G1 were conjugated with the GM3 isothiocyanate derivative to give hypervalent thiourea derivatives containing four and eight GM3 trisaccharide residues. Lactosamine- and GM3-containing glycopolymers were successfully prepared by incorporating the corresponding amine-terminated glycosides into pre-formed active poly(N-oxysuccinimidyl acrylate). The grafting polymerization reactions are carried out under mild conditions and afford fair to good yields.