Four analogues of the Lewis X trisaccharide antigen (β-D-Galp(1→4)[α-L-Fucp(1→3)]-D-GlcNAcp) in which the galactosyl residue is modified at O-4 as a methyloxy, deoxychloro, deoxyfluoro or deoxy were synthesized. The preparation of the modified 4-OMe, 4-Cl, 4-F and 4-H trichloroacetimidate galactosyl donors is described as well as their use in the glycosylation of an N-acetylglucosamine glycosyl acceptor. The resulting disaccharides were deprotected at O-3 of the glucosamine residue and fucosylated giving access to the desired protected Lewis X analogues. One step global deprotection (Na/NH3) of the protected 4”-methoxy and 4”-deoxy analogues, and two step deprotections (removal of a p-methoxybenzyl with DDQ, then Zemplén deacylation) of the 4”-deoxychloro and 4”-deoxyfluoro protected Lex analogues gave the desired compounds in good yields. The relative binding energies of the 4” manipulated Lewis X methyl glycoside analogues for anti-Lewis X mAb SH1 were determined using competitive ELISA procedures. The binding experiments revealed that substitution of the 4” site with a deoxychloro, deoxyfluoro or deoxy function had a large differential change in the free energy of binding; yet they did not completely abolish cross reactivity with native Lewis X. Substitution with a methyloxy function eliminated recognition by anti-Lewis X monoclonal antibody SH1. / NSERC
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OGU.10214/4009 |
| Date | 14 September 2012 |
| Creators | Moore, Christopher |
| Contributors | Auzanneau, France-Isabelle |
| 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 |
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