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|
|Official Date:||September 2011|
|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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