Synthesis of Glycopeptides and Neoglycopeptides using Click Chemistry

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dc.contributor.advisor Brimble, M en Lee, Dong en 2011-07-19T23:37:31Z en 2011 en
dc.identifier.uri en
dc.description.abstract This thesis describes an investigation towards the syntheses of glycopeptides and neoglycopeptides using click chemistry. The first part of this research project deals with the synthesis of a library of fluorescent-labelled glycopeptides 2.2-2.8 using automated microwave-enhanced Fmoc SPPS. This involved the synthesis of GalNAca1-O-Ser/Thr building blocks 2.23a/2.23b and subsequent incorporation into stepwise Fmoc SPPS. The next chapter deals with the synthesis of neoglycopeptides using a chemoselective Cu(I)-catalyzed 1,3-dipolar cycloaddition (click chemistry) between organic azides and akynes. Collaboration with the Kent laboratory enabled the assimilation of knowledge and training in manual in situ Boc SPPS protocols for the synthesis of peptides. NCL and click chemistry were combined in a one-pot fashion to prepare a di-glycosylated neoglycopeptide 3.28 with high efficiency, while establishing the compatibility of click reaction conditions with various functional groups involved in the synthesis of peptides using manual in situ Boc SPPS. The following chapter describes the synthesis of click analogues 4.55-4.60 of the MUC1 sequence using microwave enhanced Fmoc SPPS and optimized click conditions. These conditions involved the use of excess copper(I) in a chaotrope-containing solvent, 6 M GnHCl, and have also found that microwave irradiation enhanced the rate of click reaction. The last chapter describes synthetic studies towards a click analogue of erythropoietin (EPO), a highly glycosylated protein involved in the regulation of red blood cell production. For this study, all the skills that had been acquired to this point were used. The peptidethioester fragments 5.31-5.34 were prepared using manual in situ Boc SPPS strategy, whereas the C-terminal acid fragment 5.35 was synthesized using automated microwave-enhanced Fmoc SPPS. Propargylglycine residues 3.8 were installed in the peptide sequence where glycosylations usually occur in the native form, and different monosaccharide sugar-azides 3.14, 4.42 and 5.30 were synthesized to effect click reactions with the propargylated EPO peptides. The one-pot NCL and click chemistry strategy developed with the Kent laboratory was also utilized for maximum efficiency. The synthetic route towards the desulfurized click EPO1-5 neoglycopeptide 5.51 was optimized using monosaccharide sugar-azides, thus future work involves the synthesis of more complex glycans to attach onto the peptide backbone using click chemistry. en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.title Synthesis of Glycopeptides and Neoglycopeptides using Click Chemistry en
dc.type Thesis en The University of Auckland en Doctoral en PhD en
dc.rights.holder Copyright: The author en
pubs.elements-id 214996 en
pubs.record-created-at-source-date 2011-07-20 en

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