Romero-Canelón, Isolda (2012) Design and mechanism of action of organometallic anticancer complexes. PhD thesis, University of Warwick.

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Abstract

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.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Organometallic chemistry, Antineoplastic agents, Organometallic compounds -- Therapeutic use, Transition metal complexes -- Therapeutic use, Ruthenium
Official Date:	August 2012
Dates:	Date Event August 2012 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Sadler, P. J.
Extent:	viii, 325 leaves : charts.
Language:	eng

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