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Title: Aqueous solution chemistry of ruthenium arene anticancer complexes
Author: Lough, Julie Ann
ISNI:       0000 0004 2700 4298
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2010
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Metal complexes currently are currently of much interest in the field of anticancer drug development. Platinum complexes such as cisplatin, are now widely used in the clinic and have led to a focus on the synthesis of new classes of other metal-based complexes, such as ruthenium anticancer drugs. In order to understand the mechanism of action of these complexes and to improve structureactivity relationships thereof, a comprehensive study of the solution chemistry is important. In this thesis the mechanism and kinetic detail of the exchange of amino protons on one such class of complex, [(η6-biphenyl)Ru(N,N’- ethylenediamine)Cl]+ was investigated in detail. Stereospecific assignment of NH protons was carried out by NOESY NMR on a pyridine adduct [(η6- biphenyl)Ru(N,N’-ethylendiamine)(N-pyridine)]2+. Using 1H and 2H NMR spectroscopy, rates of exchange were observed at different pH values, temperatures and ionic strengths a series of N-H/2H exchange reactions were studied and the data collected. The data are consistent with an exchange mechanism involving proton abstraction from the amine, followed by favourable reprotonation on the lowerface (relative to the overhanging arene) of the Ru(N,N’- ethylendiamine) five membered ring. In chlorido complexes this leads to the exchange of lower proton at a rate of three times that of those on the upperface at 298 K. To investigate the effects of electron density on the ruthenium on the exchange rates a series of π-donor pyridine ligands (pyridine, 4-methylpyridine, 4- tert-butylpyridine, and 4-methoxypyridine) in the place of the chloride were studied. The exchange rates were also investigated and showed a correlation between the basicity of the pyridine derivative and the favourability of exchange on the lower face, increasing this bias upto 11 fold. Density functional theory calculations suggests that there is an overlap between the p-orbital of the (ethylenediamine) nitrogen and the π*-antibonding orbital on the Ru-N(Pyridine) bond and σ*- antibonding orbital on the Ru-Cl bond, in their respective complexes. This overlap is proposed as a stabilising force on the deprotonated nitrogen allowing for a negative charge to be more stabile in one lobe of the p-orbital preferential to another. Following abstraction of the proton, the lone pair on the nitrogen is stabilised by an antibonding orbital, the top face less is susceptible to proton addition. Since DNA is a potential target for these complexes, the changes in shape induced by metal binding were investigated using Ion-Mobility Mass Spectrometry for the first time. Also in this work, the first ion-mobility mass spectrometry studies of the collisional cross sections (CCSs) of small complexes (<100 Å2) is also presented. This was developed using a new glycine based calibrant. Following binding of [(η6-biphenyl)Ru(N,N’- ethylenediamine)Cl]+ to the DNA hexamer d(CACGTG) changes in CCS values between ruthenated and non-ruthenated hexamers were studied. The change in CCS between these was not additive and suggestive of some folding or intercalation occurring upon ruthenium binding. Finally, attempts were madeto investigate shape change induced in DNA by binding to cisplatin using Förster Resonance Energy Transfer Methods are described. To date these results are inconclusive but work in this field is ongoing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry