Date of Award

11-5-2020

Publication Type

Master Thesis

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

John Trant

Keywords

Glycolipids, anti cancer vaccine, C-glycoside, TF antigen, Tn antigen, tumour-associated carbohydrate antigens

Rights

info:eu-repo/semantics/openAccess

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Abstract

Cancer cells express unique carbohydrate signatures on their surfaces known as tumour-associated carbohydrate antigens (TACAs). These antigens are not typically found on healthy cells and therefore are promising targets for immunotherapy using adap-tive immune response tools. If the immune system could theoretically be “trained” to tar-get this molecule, then the immune system could be used to help eradicate any cancer cells from the host. A problem with carbohydrate-based targets is they are not stable in the body because of their inherent acetal functionality: the glycosidic bond. This research aims to remove the unstable acetal functionality in carbohydrates by replacing the exocy-clic anomeric oxygen with a methylene group (C-glycoside) to make new N-Fmoc pro-tected acetal-free C-glycoside analogues of the Tn antigen, a TACA found on many tu-mor cells. Removing the labile functionality should result in a greatly enhanced lifetime and bioavailability relative to the native system with no likely loss in recognition specifici-ty as the exocyclic oxygen is not generally involved in molecular recognition events. The Thomsen-Friedenreich antigen is another tumour-associated carbohydrate, which is found on specific types of cancer cells, such as CD34+ T-cells in leukemia and sarcoma, as well as CD 44+-cells in colon and breast cancers. The application of this anti-gen confronts the same limitation as to the Tn antigen. In order to be more effective, it has to be modified to increase its stability and have a higher chance of getting to the tar-get and inducing the required immune response. The synthesis of a fully acetal-free TF is challenging because of the unique 1,3-β one carbon linkage between the galactose and N-acetyl galactosamine moieties. Through the removal of both the exocyclic oxygens in the anomeric position and the linkage between the two sugar moieties, and replacing them with methylene groups, the stability of this antigen under biological conditions in the body greatly increases, and as a result, can better activate the immune system. This type of double C-glycoside-amino acid conjugate has never been reported in the literature for any carbohydrate. This thesis will discuss significant progress towards the synthesis of this promising, but challenging, fully acetal-free TF antigen. The next portion of the thesis expresses the synthesis of two glycolipids isolated from S. pneumoniae, the leading cause of neonatal sepsis and meningitis. Two main frac-tions of antigenic S. pneumoniae glycolipids were identified. One contains a monosaccha-ride, and the second fraction contains a disaccharide. Both the monosaccharide and the disaccharide appear capable of activating invariant natural killer T cells (iNKT), a subclass of white blood cells that produce non-specific cytokines whose activation can lead to a systemic uncontrolled immune response. The total synthesis of both the mono- and the disaccharide will be discussed in this thesis and the biological activity of these synthe-sized saccharides will be measured in order to confirm their structures, which have never been examined. The next part of the thesis reports the efforts toward the study of the limitations of the selective removal of acetates in the presence of long-chain esters. This area of re-search remains under development as selective deprotection of the acetyl group, especial-ly in the pyranose sugar moiety is largely unexplored. The final section of the thesis outlines the synthesis of an acetylated lactose bear-ing free hydroxyl groups at the C-6 and C-6΄ for attachment to conjugated polymers, with applications in electronic devices.

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