Soldevila Barreda, Joan Josep (2014) Design of catalytic organometallic anti-cancer drugs. PhD thesis, University of Warwick.

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Abstract

This thesis is concerned with the design of organometallic half sandwich complexes which can catalyse the conversion of oxidised coenzyme nicotinamide adenine dinucleotide to its reduced form. The coenzyme pair NAD+/NADH is involved in many biological processes, such as regulation of the redox balance, and DNA repair. Disturbance of the NAD+/NADH ratio can lead to cell death. In particular, cancer cells are under constant oxidative stress and therefore might be more susceptible to changes in the NAD+/NADH levels.

A series of neutral Ru(II) complexes of the type [(η6-arene)Ru(N,N’)(L)] (arene = p-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), benzene (bn); N,N’ = N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-toluensulfonamide (TsEn), or N-(2-aminoethyl)-4-methylensulfonamide (MsEn)) were synthesized and fully characterized. The complexes were shown by 1H-NMR to catalyse region-selectively the transfer hydrogenation of NAD+ to 1,4-NADH. Comparison of the turnover frequencies (TOF) for the complexes show a trend in which a decrease in catalytic activity with the arene ligand follows the order bn > bip > p-cym > hmb and TfEn > TsEn > MsEn. Complex [(η6-bn)Ru(TfEn)Cl] (12) was found to be the most active with a TOF of 10.4 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied for complex [(p-cym)Ru(TsEn)Cl] (2).

The monotosylate ethylenediamine Ru(II) complexes were used to carry out, for the first time, transfer hydrogenation reactions in cellulo (A2780 ovarian cancer cells) using formate as a hydride source. The antiproliferative activity of six complexes on co-administration with non-toxic doses of sodium formate were studied. A significant potentiation of the antiproliferative activity by formate was observed. The concentrations of NAD+ and NADH in cells showed an important reduction in the NAD+/NADH ratio. This study demonstrates that it may be possible to use catalytic transfer hydrogenation as a strategy for multi-targeted redox mechanisms of action for anticancer drugs.

In order to compare the anticancer mechanism of the monotosylate ethylenediamine Ru(II) complexes with the corresponding ethylenediamine (en) complexes, DNA binding studies were carried out. The complexes were shown to bind to nucleobases only moderately strongly and no direct coordination to calf thymus DNA was observed. The complexes can destabilize DNA, but they display low affinity towards DNA, which suggests that DNA is probably not involved in the mechanism of these family of compounds.

Interaction of complex [(p-cym)Ru(TsEn)] (2) with glutathione (GSH) was also studied. The complex undergoes ligand substitution. Two Ru(II) dimers were formed as the main products of the reaction: ([((p-cym)Ru)2(μ-GS)3] and [((p-cym)Ru)2(μ-GS)2]). These dimers share structural similitudes with other reported Ru(II) arene anticancer drugs, which suggests that they could be responsible for the moderate antiproliferactive activity of complex 2.

A series of CpxRh(III) (CpX = CpXPhPh, CpXPh or Cp*) complexes containing en or TfEn were synthesised and fully characterised. The complexes were shown to catalyse regioselectively the transfer hydrogenation of NAD+ to 1,4-NADH with higher TOF than their Ru(II) analogues. Rh(III)-en compounds were shown to be more active than the Rh(III)-TfEn analogues. The nature of the Cpx ring was shown to influence significantly the catalytic activity of the complexes following the trend: CpXPhPh > CpXPh > Cp*. Complex [(CpXPhPh)Rh(en)Cl]+ (19) was the most active, with a TOF of 24.2 h-1. The catalytic cycle for the transfer hydrogenation reaction was studied using complex [(Cp*)Rh(en)Cl]+ (17) and compared to that of the Ru(II) analogues, and was found to be similar. Antiproliferative activity of the complexes in combination with formate, in A2780 cells, was investigated, but the potentiation due to the transfer hydrogenation was much lower than that obtained with Ru(II) compounds.

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):	Organometallic compounds, Antineoplastic agents
Official Date:	2014
Dates:	Date Event 2014 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Sadler, P. J.
Extent:	xiii, 274 leaves : illustrations, charts
Language:	eng

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