Year

2021

Degree Name

Doctor of Philosophy

Department

School of Chemistry and Molecular Bioscience

Abstract

Upregulation of sialyltransferases (STs), the enzymes responsible for the addition of sialic acid to growing glycoconjugate chains, and the resultant hypersialylation of tumour cell surfaces is an established hallmark of several cancers including lung, breast, ovarian, pancreatic and prostate cancer. Sialic acid regulating enzymes have been increasingly implicated in processes leading to tumour cell growth and metastasis, as well as linked to multi-drug and radiotherapy resistance.

These factors have led to the inhibition of sialylation as a potential new anti-metastatic cancer treatment strategy. Of particular interest are the transition-state analogues, which mimic the planar oxocarbenium-like transition state of the ST mechanism. These compounds have been the most potent ST inhibitors to date, although they suffer from pharmacokinetic and cell-permeability issues, due to the charged phosphodiester linkage which is subject to cleavage by phosphatase enzymes. The transition state analogues are also subject to synthetic accessibility issues from the cytidine nucleoside, which often requires many protection and deprotection steps in their synthesis. In order to improve upon these pharmacokinetic and synthetic accessibility issues, replacing the phosphodiester linkage with a neutral linker such as a carbamate or triazole has been investigated, along with the replacing the cytidine nucleoside with uridine. Another consideration in the design of ST inhibitors is the search for selectivity between ST subtypes, as global ST inhibition has resulted in detrimental effects in in vivo mouse models.

FoR codes (2008)

0304 MEDICINAL AND BIOMOLECULAR CHEMISTRY

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.