Since the discovery of cisplatin, numerous attempts have been made to emulate its activity while reducing its collateral toxicity. Coordination complexes based on a wide number of transition metals have been developed in the search for improved bioavailability, selectivity and reduced adverse side-effects. Ruthenium(II) complexes have been widely developed in this field as a viable alternative to platinum chemotherapeutics. This thesis is concerned with the synthesis, characterization and biological evaluation of three series of novel half-sandwich complexes of the general formula [RuII(arene)(X)(YZ)]n+. These piano-stool RuII complexes have been designed as to allow the fine-tuning of their chemical and biological properties. In the first two series, the arene unit has been varied between p-cymene, biphenyl and terphenyl to investigate the correlation between hydrophobicity and antiproliferative activity, while the N,N-imino pyridine chelating ligand, YZ, has been modified to include either a higher number of aromatic units that could allow better DNA intercalation or substituent groups that could affect the overall charge distribution in the complex. Finally, the monodentate ligand, X, is either chloride or iodide. These compounds have been fully characterised by NMR, MS and elemental analysis. Their aqueous behaviour has been investigated together with the extent of 9-EtG binding, as an indication of the possible interaction with nucleobases. The antiproliferative activity of these novel RuII complexes was determined, several of them show promising IC50 values, in the low μM range, against ovarian, colon, lung and breast cancer cell lines, in many cases the activities observed are better than cisplatin. The pathways for cellular accumulation were investigated. Complexes with an I as the monodentate ligand, X, exhibit partial energy-independent uptake. Overall results indicate that the novel RuII complexes synthesised in this thesis are most likely to be multi-targeted and that their mechanism of action depends to a great extent on the nature of the monodentate ligand, X. Two particularly active complexes in these series include the impy-NMe2 ligand as YZ chelate. These have been compared to their isostructural azopyridine analogues and also to their OsII equivalents. In this case, experiments were designed to study the activation of landmark events that lead to apoptosis, allowing contrasting the effects of different metal centres (Ru vs Os), isoelectronic ligands (impy-NMe2 vs azpy-NMe2) and monodentate ligands (Cl vs I). Results indicate that the molecular pathway followed by the iodido complexes is p53-independent. In comparison, the chlorido analogues activate the intrinsic apoptotic pathway and their activity relies on the existence of this tumour suppressor. DNA intercalation was also evaluated as a possible mechanism of action. Finally, the third series includes inactive RuII complexes with tetrahydroquinoline derivatives, which were found to enhance the activity of platinum drugs in clinical use. These promising preliminary results in the use of RuII complexes in combination therapy open a world of possibilities for the dose-reduction of platinum-chemotherapeutics.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:575013 |
| Date | January 2012 |
| Creators | Romero-Canelón, Isolda |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/55211/ |
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