Drawbacks associated with anticancer chemotherapeutic cisplatin include tumour drug resistance, non-effectiveness against all tumours and lack of tumour-specificity resulting in severe side-effects (e.g. nausea, hair loss and kidney toxicity). The use of other metals such as transition metals rutheniumandosmium, may address the problems associated with platinum drugs and have received increased interest over the years. In this thesis the biological activity and aqueous solution chemistry of half-sandwichosmium (II) compounds of the type [(arene)OsII(X)(YZ)] n+ is explored. Chelating ligands containing nitrogen or nitrogen and oxygen donor atoms (N, NandN, O-chelatingligands) are investigated. It is shown that the chelating ligand has a large effect on the aqueous reactivity of the complexes. The introduction of functional groups on the chelate allowed for the ‘fine-tuning’ of the aqueous reactivity and nucleobase binding of the complexes. Also the nature of the coordinating arene was found to have an important effect on their biological activity. This could be rationalised by increased hydrophobicity with more extended arenes such as biphenylandtetrahydroanthracene, resulting in increased cellular uptake and increased cytotoxicity. Conjugating cell penetrating peptides to the complexes resulted in improved biological properties and opened a new way for functionalisation of the compounds. Several compounds reported in this thesis exhibit promising activity in the ovarian, colon and lung cancer cell lines and some could overcome cisplatin resistance in ovarian cisplatin resistant cell lines. Initial studies revealed cell death via apoptosis and the possible involvement of mitochondria in the apoptotic pathway. These results point to a novel pathway of activation for these complexes which is advantageous for addressing chemoresistance and effectiveness to oher types of cancers. This work shows that the biological properties of these compounds can be tuned by choice of ligands and also provides initial evidence for a novel pathway of activation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:521395 |
| Date | January 2010 |
| Creators | Rijt, Sabine H. van |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/3213/ |
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