Martin, Harlei (2019) The Synthesis and Biological Evaluation of Anti-Adhesion Glycoconjugates Against Opportunistic Pathogenic Candida albicans. PhD thesis, National University of Ireland Maynooth.

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Abstract

Anti-adhesion therapy can be used to prevent infectious diseases caused by fungi and bacteria. Anti-adhesion ligands interfere with the ability of the fungi or bacteria to adhere to cells in the host organism. Newformsof therapy areneeded sincethe inappropriate use of antifungal agents and antibiotics has led to an increase in fungal and bacterial strains resistant to conventional formsof treatment.In this thesis, anti-adhesion compounds of Candida albicansto buccal epithelial cells (BEC) are considered. It was found that glycomimetics built around aromatic scaffolds could be potential anti-adhesion ligands. Using synthetic carbohydrate chemistry and Copper-Catalyzed Azide-Alkyne Cycloaddtion (CuAAC) chemistry, a first generation of monovalent, divalent and trivalent anti-adhesion ligands were synthesised. After this initial SAR (Structure Activity Relationship) study a divalent galactoside was identified as the lead compound, capable of displacing 50 % of yeast cells already attached to the BECs. Fluorescence studies suggest that this compound may bind to structural components of the fungal cell wall. In the pursuit of increasing the potency of this lead compound, anti-adhesion ligands with alternative scaffolds were synthesised and evaluatedin biological assays. It was found that the squaramide derivatives did not improve the anti-adhesive properties of the original compounds. However, a norbornene derivative showed better results than the lead compound in two of the assays and had the ability to displace 45 % of yeast already attached to the BECs. To exploit the ‘Multivalent/Chelate Effect’ and increase the potency of the divalent galactoside, multivalent displays of the lead compound were then synthesised. The lead compound was attached to different scaffolds using a triethyl glycol linker and CuAAC chemistry. This resulted in glycoclusters and glycodendrimers having different valencies (three to sixteen copies of the lead compound), flexibilities and carbohydrate presentation.The ultimate aim of this research is to identify the Candida cell wall component responsible for the adhesion process with which the lead compound is interacting. Photoaffinity labelling (PAL) may be used to identify target proteins. PAL probes containing two different phototags, a benzophenone and a diazirine derivative, were synthesised. The phototags were covalently linked to the lead compound using coupling chemistry and aza-Micheal addition reactions.

Item Type:	Thesis (PhD)
Keywords:	Synthesis; Biological Evaluation; Anti-Adhesion Glycoconjugates; Candida albicans;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	16884
Depositing User:	IR eTheses
Date Deposited:	24 Jan 2023 14:13
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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