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Mono and dinuclear ruthenium complexes as anti-cancer therapeutic leads

Jarman, Paul J (2015) Mono and dinuclear ruthenium complexes as anti-cancer therapeutic leads. PhD thesis, University of Sheffield.

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Abstract

This thesis details chemistry and cell biology based interdisciplinary studies on a series of ruthenium based biomolecular probes that were synthesised and investigated for their anti-cancer properties. The previously reported mononuclear ruthenium-based [(phen)2Ru(tpphz)]2+ and three related new complexes were synthesised as a series to explore DNA binding. Binding to genomic DNA in vitro was confirmed for all complexes utilising their luminescence properties – specifically the DNA light switch effect via aqueous luminescence titrations. Cellular activity in the model of cisplatin sensitive/resistant A2780/A2780cis human ovarian carcinoma was then studied, with IC50 concentrations determined for each complex in each cell line and adequately repeated. This revealed a clear series of toxicities comparable to the level of cisplatin, furthermore a variety of positive and negative cross resistance profiles were observed. Time lapse microscopy data was then obtained for each complex and cell line permutation to visualize the mode of cell death, and a proteomic study was conducted with the aim of gathering more mechanistic detail behind the cell death pathway. After optimisation of a consistent workable protocol, photocytotoxicty was also investigated. Although this work was primarily with the ruthenium-rhenium and ruthenium-platinum binuclear complexes of the original series, further systems incorporating ruthenium-rhenium molecules were also investigated. Interestingly, these studies revealed contrasting phototoxic activity and a particularly impressive phototoxic index score for a Ru2Re2 macrocyclic cation.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Science (Sheffield) > Chemistry (Sheffield)
The University of Sheffield > Faculty of Science (Sheffield)
Depositing User: Mr Paul J Jarman
Date Deposited: 23 Jun 2016 11:15
Last Modified: 23 Jun 2016 11:15
URI: http://etheses.whiterose.ac.uk/id/eprint/12213

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