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    Synthesis and Biological Evaluation of Anti-Cancer Platinum(IV) Glycoconjugates using CuAAC “Click” Chemistry

    Moynihan, Eoin (2023) Synthesis and Biological Evaluation of Anti-Cancer Platinum(IV) Glycoconjugates using CuAAC “Click” Chemistry. PhD thesis, National University of Ireland Maynooth.

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    Cisplatin is the most widely used chemotherapeutic drug worldwide. Unfortunately, its use is hampered by severe dose-limiting side effects, intrinsic and acquired resistance and high toxicity. Furthermore, a major drawback associated with cisplatin therapy is its lack of selectivity for cancer cells with respect to healthy tissues. One method to circumvent these side effects is to modify the chemical structure of the drug with selective targeting vectors whose receptors are overexpressed on the cell membrane of cancer cells. One example of this are sugars which are recognised by glucose transporters (GLUT). In this thesis, a series of glyco-functionalised platinum(IV) anticancer pro-drugs (where the sugar is glucose or galactose) are described, which were synthesised and characterised with the aim to create a library of novel selective metal-based chemotherapeutics. These complexes contain the Platinum metal centre in the +4 oxidation state, which have been shown to be more stable with respect to the classical Pt(II) complexes such as cisplatin. Our ligands consist of a combination of protected and deprotected glucose and galactose moieties conjugated to the axial positions of platinum(IV) complexes centre through the anomeric C1, and C2 positions, using CuAAC “click” chemistry. This thesis is divided in five chapters, with Chapter 1 containing an introduction outlining the aims and objectives of this thesis, together with a literature review which summarises the novelty of this research topic. Chapter 2 reports the synthesis, characterisation and biological evaluation of a series of C1-acetylated Pt(IV) complexes which show similar activity to cisplatin against OS cell lines (SAOS-2, U-2 OS, MG63), but lack selectivity for cancer cells. This is probably due to the presence of the acetyl protecting groups that hamper the complexes’ ability to be internalised into the tumoral cells through GLUTs. In Chapter 3, a novel series of C1 de-acetylated (free sugar) Pt(IV) pro-drug derivatives are described. Like their acetylated counterparts, these complexes show similar cytotoxicity to cancer cells (MG63 and SAOS-2) as the reference drug cisplatin but, when incubated with healthy cells (hFOBs), they show a reduced cytotoxicity, ascribable to the uptake through GLUTs. Chapter 4 outlines our efforts to enhance the selectivity for cancer cells by functionalising the carbohydrate moiety in the C2 position, which has been shown to improve the drug uptake by GLUTs when compared to its C1 isomers. This series of complexes were found to display superior activity in comparison to cisplatin against cancer cells (SAOS-2, U-2 OS, MG63, MDA-MB-468, U-87 MG). Finally, Chapter 5 details the synthesis and characterisation of multivalent galactose ligands which were intended to be coupled to our Pt(IV) scaffold. These ligands target the asialo-glycoprotein receptor (ASGPR), rather than GLUT, for the treatment of hepatocellular carcinoma (HCC), the most common type of liver cancer in Asia and Africa. Synthetic problems are encountered during the experimental work which prevent the formation of the final complexes pure enough for biological studies. However, future work and perspectives are discussed in this chapter that may result in the successful formation of these complexes.

    Item Type: Thesis (PhD)
    Keywords: Synthesis; Biological Evaluation; Anti-Cancer Platinum(IV) Glycoconjugates; CuAAC “Click” Chemistry;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 18304
    Depositing User: IR eTheses
    Date Deposited: 21 Mar 2024 16:55
      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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