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Design, synthesis and activation of ruthenium arene anticancer complexes
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Betanzos Lara, Soledad (2010) Design, synthesis and activation of ruthenium arene anticancer complexes. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b2482432~S15
Abstract
The synthesis and characterisation of RuII complexes of the form [(η6-arene)Ru(N,N')X]+ (where N,N' is a bidentate chelating ligand and X is a halogen) are
described; including the X-ray crystal structures of four of these complexes. The hydrolysis
rates at 310 K of the complexes vary over many orders of magnitude and in some cases are
followed by partial arene loss. Density Functional Theory (DFT) calculations suggest that the
aquation mechanism occurs via a more associative pathway. The significant cytotoxic activity
towards A2780 human ovarian cancer cells of some of the complexes is found to be
dependent on the chelating ligand. Selective binding to 9-ethylguanine (9-EtG) but not to 9-
ethyladenine (9-EtA) is observed in aqueous solution at 310 K in all cases. The X-ray crystal
structure of a RuII arene 9-EtG adduct is also described. DFT calculations show that the 9-
EtG nucleobase adducts of all complexes are thermodynamically preferred compared to those
of 9-EtA. Preliminary CT-DNA studies in cell-free media suggest that some of these
complexes can interact with DNA.
A family of piano-stool RuII arene complexes of the form [(η6-arene)Ru(N,N')(L)]2+
(where N,N' is a chelating ligand and L is a pyridine or a pyridine-derivative), that can
selectively photodissociate the monodentate ligand (L) when excited with UVA or visible
light is described. The X-ray crystal structures of five of these complexes are also discussed.
Their photoactivation allows the formation of a reactive aqua species that otherwise would
not form in the dark. Results from TD-DFT calculations suggest that all the RuII pyridine
complexes follow a relatively similar L-ligand photodissociation mechanism, likely to occur
from a series of 3MC triplet states. It is shown how light activation can be used to
phototrigger binding of these complexes to nucleobases with specific preference towards 9-
EtG over 9-EtA. CT-DNA studies suggest that photoirradiated complexes interact with DNA
via a combined coordinative, intercalative, and monofunctional binding mode. Some of the
complexes are also cytotoxic against A2780 human ovarian cancer cell line in the absence of
irradiation.
The possibility of photo(triggering) hydride-transfer reactions using RuII arene
complexes, NAD+, and formate as the hydride source under biologically relevant conditions
is shown. The reactions occur either upon the spontaneous hydrolysis of a Ru–Cl bond in
complexes of the form [(η6-arene)Ru(N,N')Cl]+ (where N,N' is a bidentate chelating ligand)
or upon the photolysis of a Ru–N(Py) bond in [(η6-arene)Ru(N,N')Py]2+ (Py is pyridine). A
mechanism involving the formation of a stable formate adduct followed by a hydrogen β-
elimination is proposed. It is also demonstrated how a hydride-transfer from 1,4-NADH to
some RuII arene chlorido complexes can occur in aqueous solution.
Neutral RuII arene complexes of the form [(η6-arene)Ru(NH3)Cl2] which are
constitutional analogues of cisplatin were synthesised by a novel synthetic method. These
analogues display extensive H-bond interactions in the solid state as shown by X-ray crystal
structures determination and their biexponential hydrolysis rates at 310 K vary over many
orders of magnitude. The complexes are found to readily form mono- and di-guanine adducts
upon hydrolysis but are not cytotoxic against the A2780 human ovarian cancer cell line up to
the maximum concentration tested (100 μM).
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry | ||||
Library of Congress Subject Headings (LCSH): | Ruthenium, Aromatic compounds, Antineoplastic agents | ||||
Official Date: | September 2010 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Department of Chemistry | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Sadler, P. J. | ||||
Sponsors: | European Union (EU) ; University of Warwick ; Overseas Research Students Awards Scheme (ORSAS) ; Consejo Nacional de Ciencia y Tecnología (Mexico) (CONACYT) | ||||
Extent: | ix, 289 leaves : ill., charts | ||||
Language: | eng |
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