PolySialic acid (polySia) is a linear carbohydrate homopolymer of α- 2,8-linked sialic acids and a posttranslational modification of NCAM (neural cell adhesion molecule), biosynthesized by combined action of two polysialyltransferase enzymes, ST8SiaIV(PST) and ST8SiaII(STX).
PolySia alters NCAM-dependent cell adhesion that is crucial for the CNS development. In adulthood, polySia expression is largely absent persisting only in areas of the brain associated with neuronal plasticity. Significantly, a number of malignant tumours re-express polySia and there is considerable evidence that its presence is related to higher malignancy, invasion and metastasis.
The hypothesis underpinning this project is that inhibition of polySia biosynthesis will prevent (or reduce) tumour cell migration and invasion, thereby reducing the incidence of metastasis, which will lead to higher patient survival.
The work reported in this thesis describes efforts towards the synthesis polysialyltransferase inhibitors that are structural analogues of CMP-Neu5Ac, the natural substrate. Specifically, development of methodology to synthesise building blocks suitable for conjugation as inhibitors is described.
Quinic acid-based substrate analogues were explored, with a focus on development of chemistry to achieve substitution of C1-OH. Several protected quinic acid-based compounds were synthesized, and deoxygenation of the C1-OH through the use of a Barton-McCombie reaction was accomplished successfully, allowing an attempt to introduce different aliphatic groups at C1 position using the Mukayiama reaction. Synthesis of a cytidine building block, suitable for conjugation to either quinic acid or sialic acid is also reported. In parallel, studies towards the development of sialoside disulfide analogues are described, with novel conditions identified for their synthesis.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/13484 |
| Date | January 2013 |
| Creators | Oliveira, Inês P.F. |
| Contributors | Falconer, Robert A., Patterson, Laurence H. |
| Publisher | University of Bradford, Institute of Cancer Therapeutics, School of Life Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, research masters, MPhil |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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