Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649667
Title: Ruthenium arene azo anticancer complexes
Author: Dougan, Sarah J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Abstract:
This thesis is concerned with the design of ruthenium(II) arene anticancer complexes where the chelating ligand contains an azo-imine group (­N=N-C=N) which binds to the ruthenium to form a five-membered chelate ring. Several mononuclear complexes containing the chelating 2-phenylazopyridine ligand or derivatives thereof were found to be moderately cytotoxic towards A2780 human ovarian and A549 human lung cancer cells (IC50 18-88 μM). These complexes were found to hydrolase (Ru-C1 → Ru-OH2) slowly in aqueous solution and arene loss was a competing reaction. X-ray crystal structures revealed that the arene ligand is not as tightly bound to the ruthenium as in the case when the chelating ligand is en. Synthesis of the corresponding dinuclear analogues, where two 2-phenylazopyridine ligands were joined together via a linker, did not improve the cytotoxicity. Unlike their mononuclear analogues, the complexes appeared to undergo electrochemical reduction with radical formation in aqueous solution. An EPR spectrum of the mono-reduced anion revealed an entirely ligand based radical. Surprisingly, replacement of Cl- by I- in the mononuclear complexes led to compounds that were highly cytotoxic towards both A2780 and A549 cancer cells (IC50 1-5 μM). Interestingly these complexes were resistant to hydrolysis in aqueous solution suggesting that this class of compounds had a novel mechanism of cytotoxic action not involving activation by hydrolysis. The redox chemistry of these complexes proved to be central to their observed cytotoxicity. The complexes were rapidly reduced by the biological reductant ascorbate, catalytically oxidised the tripeptide glutathione and generated reactive oxygen species (radicals) inside A549 cancer cells. These reactive oxygen species were shown to be involved in cell death. These iodide complexes were also found to be cytotoxic towards non-cancerous WI38 human lung cells (IC50 1-6 μM) and attempts were made to target one complex specifically to cancer cells, through conjugation to transferrin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.649667  DOI: Not available
Share: