Heparin glycosaminoglycans mediate a range of biological events, including anticoagulation as well as a diversity of cell proliferation and differentiation processes. Heparin saccharides have been shown to act as inhibitors against angiogenesis and metastasis of tumour cells. This thesis describes work developing chemistry towards varying length oligosaccharide sequences with potential to offer variable sulfation patterns. The main synthetic components to this work were contribution to developing scalable syntheses of an orthogonally protected L-Iduronic acid unit and a differentially protected D-glucosamine unit. The synthetic work also evaluated a recently reported diazo transfer reagent, which allowed for earlier placement of azide protection over that of previously developed routes within the group. This provided a cheaper, more atom efficient route towards protected D-glucosamine building blocks. Glycosylation of the developed D-GlcN donor units with the L-Ido acceptor allowed the production of key disaccharides which facilitated an efficient iterative glycosylation strategy towards longer oligosaccharides, ultimately providing a differentially protected pentasaccharide. The project evaluated methods towards generating various dimeric heparin type systems through forming new O4 ether linkages between GlcN residues across various short linker fragments. The most successful of these dimerisations used a methallyl dichloride core which allowed for further derivatisation towards dihydroxylated species, the analysis of which highlighted some interesting proton NMR data. The final aspect of this project began development of chemistry towards non-reducing end-labelled oligosaccharide sequences by implementation of a masked aldehyde unit on the C4 hydroxyl of GlcN synthesised from the allylated GlcN precursor via dihydroxylation chemistry. Incorporation of this moiety (protected as a 1,2-dibenzyl glycol) within both a trisaccharide and a pentasaccharide was achieved. Further development of this chemistry should allow for late step oxidative cleavage to reveal the reactive aldehyde, potentially allowing for attachment of various amine functionalised fluorophores via reductive amination. Radiolabelling of such a species should also be possible through sodium borotritide reduction for example.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:606878 |
| Date | January 2011 |
| Creators | Broberg, Karl Rufus |
| Contributors | Gardiner, John |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/synthetic-approaches-towards-heparinoid-related-saccharides-and-derivatives(6c1366ba-82dc-43b2-9af3-294ebed56639).html |
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