Organometallic iridium anticancer complexes
Liu, Zhe (Researcher in chemistry) (2011) Organometallic iridium anticancer complexes. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2592556~S1
Cisplatin has been used to treat various types of cancers for over 30 years, however, a number of serious side-effects of cisplatin have stimulated the quest for other metal-based anticancer agents. Iridium complexes are generally thought to be too inert to possess high reactivity, and therefore, there are only a few previous reports of the antitumour activity of iridium complexes. In this thesis a wide range of organometallic IrIII cyclopentadienyl complexes of the type [(η5-Cpx)Ir(XY)Cl]0/+ (where Cpx = pentamethylcyclopentadienyl (Cp*), tetramethyl(phenyl)cyclopentadienyl (Cpxph) or tetramethyl(biphenyl)cyclopentadienyl (Cpxbiph), XY = N,N-, N,O- or C^N-chelating ligand) has been synthesised and characterised. All the complexes hydrolyse rapidly in aqueous solution. Complexes with N,N-chelating ligands readily form adducts with 9-ethylguanine but not 9-ethyladenine; C^N- or N,O-chelated complexes bind to both purines. Guanine residues are preferential binding sites for 1,10-phenanthroline complexes on plasmid DNA. Replacement of the neutral N,N-bound chelating ligand by the negatively-charged C,N-bound analogues can improve biological activity. In addition, cytotoxic potency towards A2780 human ovarian cancer cells increases with phenyl substitution on Cp*: Cpxbiph > Cpxph > Cp*. This can be rationalised by increased hydrophobicity with more extended phenyl ring, resulting in increased cellular uptake and increased intercalative ability. Notably, several complexes exhibited submicromolar anticancer activity. The interconversion of 1,4-NADH and NAD+ through hydride-transfer reactions in the presence of cyclopentadienyl IrIII aqua complexes was studied. It is shown that the IrIII aqua complexes not only converts NAD+ to 1,4-NADH using formate as the hydride source, but can also catalyse the reverse reaction with hydride donation from 1,4-NADH to a iridium centre, recovered by protonation of bound hydride with generation of H2. This work demonstrates how the aqueous chemistry, nucleobase binding and anticancer activity of the IrIII cyclopentadienyl complexes can be controlled and fine-tuned by the modification of the chelating and cyclopentadienyl ligands. The results suggest that this new class of organometalic Ir(III) complexes is well suited for development as anticancer agents.
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QD Chemistry
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
|Library of Congress Subject Headings (LCSH):||Antineoplastic agents, Iridium -- Therapeutic use, Iridium -- Analysis|
|Institution:||University of Warwick|
|Theses Department:||Department of Chemistry|
|Supervisor(s)/Advisor:||Sadler, P. J.|
|Sponsors:||University of Warwick ; European Union (EU)|
|Extent:||vii, 242 leaves : illustrations|
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