The Synthesis of Novel Sialylmimetics as Biological Probes

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Itzstein, Mark von

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Kiefel, Milton

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Typically found at the terminus of glycoconjugates, the sialic acids are ideally located to participate in carbohydrate-protein interactions that mediate important recognition phenomena. These include acting as receptors for viruses and bacteria, mediating cell-cell adhesion via lectins, and enabling cell-cell communication. N-Acetylneuraminic acid alpha(2,3)-linked to galactose is a commonly found epitope in several important cell-surface glycoconjugates, and is associated with diseases like cancer (through the upregulation of alpha(2,3)-sialyltransferases), Chagas' disease (and the involvement of Trypanosoma cruzi trans-sialidase), and rotaviral infection. The apparent strong specificity of some sialic acid-recognising proteins for substrates with N-acetylneuraminic acid alpha(2,3)-linked to galactose suggests that this interaction may be a potential target for therapeutic intervention. This thesis focuses on investigations towards the synthesis of biological probes for sialic acid-recognising proteins that naturally recognise N-acetylneuraminic acid alpha(2,3)-linked to galactose, as well as the development of potential inhibitors for rotavirus and Trypanosoma cruzi trans-sialidase. Chapter 1 provides a general introduction of sialic acids, and the proteins that recognise them, with an emphasis on their involvement in certain disease states. There is also a discussion of the involvement of sialic acids in relation to rotavirus infection, as well as the relationship of sialic acids to Chagas' disease, via the Trypanosoma cruzi trans-sialidase enzyme. Chapter 2 describes the development of an efficient synthetic route towards S-linked lactose-based mimics of N-acetylneuraminic acid alpha(2,3)-linked to galactose. The inclusion of varying functionality in the mimetic portion was designed to allow the exploration of the effects of hydrophobic, hydrophilic and sterically demanding groups upon interaction with a given biomolecule. En route to the successful synthesis of these sialylmimetics, several protecting group manipulations of lactoside were investigated, with the preparation of the key intermediate seemingly dependent on the protecting group strategy used. Furthermore, the synthesis of the metabolically stable substrate analogue of the natural substrate of Trypanosoma cruzi trans-sialidase has been described. Approaches towards the synthesis of the O-linked series of lactose-based sialylmimetics are described in Chapter 3. Several methodologies are reported, as well as protecting group manipulations, for the successful preparation of these sialylmimetics. It appears from these investigations that gaining access into the O -linked series is not as straightforward as for the S-linked series, with the reactivity of the coupling partner being a critical factor in the success of such reactions. In Chapter 4, the synthesis of galactose- and lactose-based sialosides as sialyl donors for Trypanosoma cruzi trans-sialidase has been described, as well as the preparation of an asialo acceptor molecule. These substrates were used to probe the mechanism of the enzyme using H NMR spectroscopy, aimed at investigating the hydrolysis and transfer rates of Trypanosoma cruzi trans-sialidase with a variety of sialyl donors and asialo acceptor molecules. These studies have shown that the hydrolysis of sialyl donors is slow compared to the transfer rates of sialic acid to asialo acceptor molecules, and have provided further insight into the preference of the enzyme for various substrates. The biological evaluation of some of the compounds reported in Chapters 2 and 3 is detailed in Chapter 5. The sialylmimetics were evaluated for their ability to inhibit rotavirus infection in vitro. In addition, a novel H NMR spectroscopic-based assay was developed for inhibition studies of Trypanosoma cruzi trans-sialidase with some of the compounds prepared through the course of this project, and some preliminary inhibition results have been obtained. The conclusions drawn in Chapters 2 to 5 are summarised in Chapter 6 and the future directions of this work are briefly outlined. Chapter 7 brings together all of the experimental procedures and details that support the results and observations presented in Chapters 2 to 5.

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Thesis (PhD Doctorate)

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Doctor of Philosophy (PhD)


Institute for Glycomics

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Sialic acids

novel sialylmimetics

biological probes


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