No description available.

Yes / The synthesis, characterisation and evaluation of the in vitro cytotoxicity of four indole-based half-sandwich metal complexes towards two ovarian cancer cell lines (A2780 and A2780cisR) and one normal prostate cell line (PNT2) are presented herein. Although capable of inducing catalytic oxidation of NADH and able to reduce NAD+ with high turnover frequencies, in cells and in the presence of sodium formate, these complexes also strongly interact with biomolecules such as glutathione. This work highlights that efficient out-of-cells catalytic activity might lead to higher reactivity towards biomolecules, thus inhibiting the in-cells catalytic processes.

Yes / The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate-based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non-small-cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18-electron complexes were designed with four water-soluble phosphine ligands to increase the water-solubility character of the corresponding electron-deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine-3,3',3''trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16-electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on ROS production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay. / The support of the Royal Society (University Research Fellowship No. URF150295, and RGF\EA\201001), the Academy of Medical Sciences/ The Wellcome Trust/ The Government Department of Business, Energy and Industrial/ The British Heart Foundation Springboard Award (SBF003\1170), and the CNRS is acknowledged. LRP is supported by a PhD studentship funded by the University of Bradford.

The use of metallo-pharmaceuticals, such as the platinum drugs, for cancer treatment illustrates the utility of metal complexes as therapeutic agents. Platinum group metal complexes therefore offer potential as anti-tumour agents to fight cancer. This study was aimed at synthesizing and evaluating the effects of palladium(II) and platinum(II) complexes as anticancer agents.

No description available.

Os complexos de rutênio há algumas décadas são estudados visando à aplicação em medicina, catálise e fotoquímica. Particularmente, com interesse voltado para a área médica, novos compostos têm sido desenvolvidos para substituir a cis-platina no tratamento do câncer, uma vez que este medicamento atua numa gama restrita de tipos de tumores e apresenta efeitos colaterais. O objetivo deste trabalho de pesquisa foi obter compostos polinucleares que possam reunir, em uma única espécie, duas ou três unidades de rutênio biologicamente relevantes. Compostos já conhecidos pela potencialidade antitumoral própria - cis-[RuCl2(dmso)4] e [Ru2Cl(AcO)4] - foram escolhidos como unidades de construção. Os compostos 4,4´-bipiridina e a 4-cianopiridina foram utilizadas como ligantes de ponte para unir estas unidades. Duas rotas diferentes para a obtenção dos compostos polimetalados foram propostas, sendo a escolha dependente do ligante-ponte utilizado. Três complexos precursores foram preparados modificando-se procedimentos já descritos, e novos compostos - um monômero e quatro polimetalados -foram sintetizados. Todos os complexos obtidos foram caracterizados por meio de medidas de análise elementar (CHN), espectroscopia eletrônica (UV-VIS-NIR) de soluções e de sólidos, espectroscopia vibracional (IV), e análise termogravimétrica (TGA). A técnica de 1H RMN e medidas de susceptibilidade magnética também foram utilizadas em alguns casos. / Ruthenium complexes have been studied for some decades for use in Medicine, catalysis and photochemistry. Regarding applications in the medical field, new compounds have been developed to substitute cisplatin in cancer treatment, since it has side effects and works on a restricted range of tumours. The objective of this research was to obtain polinuclear compounds that could combine, in one single structure, two or three known biologically active ruthenium units. Compounds known to exhibit antitumoral activity - cis-[RuCl2(dmso)4] and [Ru2Cl(AcO)4] - were chosen as building blocks. The 4,4´-bipyridine and 4-cianpyridine compounds were used as bridging ligands to connect these units. Two different synthetic routes were designed to obtain the polinuclear compounds being the choice dependent of the bridging ligand. Three precursors were prepared by modified - were synthesized. All obtained compounds were characterised by elemental analysis (CHN), electronic spectroscopy (UV-VIS-NIR) in solutions and solid state, vibrational spectroscopy (IR), and thermogravimetric analysis (TGA). The 1H NMR technique and magnetic susceptibility measurements were also used in some cases.

Os complexos de rutênio há algumas décadas são estudados visando à aplicação em medicina, catálise e fotoquímica. Particularmente, com interesse voltado para a área médica, novos compostos têm sido desenvolvidos para substituir a cis-platina no tratamento do câncer, uma vez que este medicamento atua numa gama restrita de tipos de tumores e apresenta efeitos colaterais. O objetivo deste trabalho de pesquisa foi obter compostos polinucleares que possam reunir, em uma única espécie, duas ou três unidades de rutênio biologicamente relevantes. Compostos já conhecidos pela potencialidade antitumoral própria - cis-[RuCl2(dmso)4] e [Ru2Cl(AcO)4] - foram escolhidos como unidades de construção. Os compostos 4,4´-bipiridina e a 4-cianopiridina foram utilizadas como ligantes de ponte para unir estas unidades. Duas rotas diferentes para a obtenção dos compostos polimetalados foram propostas, sendo a escolha dependente do ligante-ponte utilizado. Três complexos precursores foram preparados modificando-se procedimentos já descritos, e novos compostos - um monômero e quatro polimetalados -foram sintetizados. Todos os complexos obtidos foram caracterizados por meio de medidas de análise elementar (CHN), espectroscopia eletrônica (UV-VIS-NIR) de soluções e de sólidos, espectroscopia vibracional (IV), e análise termogravimétrica (TGA). A técnica de 1H RMN e medidas de susceptibilidade magnética também foram utilizadas em alguns casos. / Ruthenium complexes have been studied for some decades for use in Medicine, catalysis and photochemistry. Regarding applications in the medical field, new compounds have been developed to substitute cisplatin in cancer treatment, since it has side effects and works on a restricted range of tumours. The objective of this research was to obtain polinuclear compounds that could combine, in one single structure, two or three known biologically active ruthenium units. Compounds known to exhibit antitumoral activity - cis-[RuCl2(dmso)4] and [Ru2Cl(AcO)4] - were chosen as building blocks. The 4,4´-bipyridine and 4-cianpyridine compounds were used as bridging ligands to connect these units. Two different synthetic routes were designed to obtain the polinuclear compounds being the choice dependent of the bridging ligand. Three precursors were prepared by modified - were synthesized. All obtained compounds were characterised by elemental analysis (CHN), electronic spectroscopy (UV-VIS-NIR) in solutions and solid state, vibrational spectroscopy (IR), and thermogravimetric analysis (TGA). The 1H NMR technique and magnetic susceptibility measurements were also used in some cases.

Structural and mechanistic complexities of copper-dioxygen systems have attracted much attention in the field of bioinorganic chemistry, both in model systems and trapped protein intermediates. The research presented herein is focused on model and naturally occurring metallopeptide systems, from its design to catalysis. Copper is used as the coordinating metal ion, with cobalt and zinc as probes for metal binding. The bioinorganic chemistry of copper proteins and its coordination and spectroscopic properties are briefly discussed in chapter 1. The next two chapters are centered on the de novo design of a minimalistic metallopeptide system with an amino acid sequence of RHHPPHHE. Structural characterization of the peptide by means of CD and NMR spectroscopy techniques are presented in chapter 2, suggesting a characteristic beta-turn structure in its apo and di-metal bound form. The designed metallopeptide exhibits catecholase activity, which is presented in chapter 3. The data suggest the presence of two mononuclear copper active sites, exhibiting specificity towards the oxidation of catecholamine substrates. Similarly, the catecholase activity has been previously observed in copper complexes of Alzheimer's disease related peptide beta-amyloid, exhibiting metal-centered redox chemistry. The metallo-(beta-amyloid); complexes are the hallmark Alzheimer's disease and have been attributed to the generation of reactive oxygen species causing oxidative stress. Thus, inhibition of the observed oxidative activities was investigated. Probing the role of phosphate moieties in various compounds as potential inhibitors against the induced oxidative stress is presented in chapter 4. The phosphate analogs of the studied compounds exhibit more pronounced potency, where mutation of the beta amyloid peptide at Arg-5 and Lys-16 give insight into the interactions of the side chains of Arg and Lys with the phosphate moiety. 31P NMR relaxation studies further support the binding/interaction of phosphate with the Cu(II)-(beta-amyloid); complexes. The correlation of phosphate moiety binding/activity will allow for the design of more potent inhibitors toward the Cu(II)-(beta-amyloid); induced oxidative stress.

[FeFe]-Hydrogenases (H2ases) are metalloenzymes that can catalyze the reversible reduction of protons to molecular hydrogen as part of the metabolism of certain cyanobacteria and green algae. Due to the low availability of the enzyme, synthetic complexes that mimic the natural active site in structure, function and activity are highly sought after. In this thesis, a number of [FeFe]-H2ases active site model complexes were synthesized to answer open questions of the active site and to develop unprecedented bio-inspired proton reduction catalysts. The first part describes the synthesis and the protonation properties of a [Fe2(μ-adt)(CO)4(PMe3)2] (adt = azadithiolate) complex which contains two basic sites that are similar to those found in the enzyme active site. Unusual kinetic factors give rise to four discrete protonation states. The twofold protonated state is the first model complex that simultaneously carries a proton at the azadithiolate nitrogen and a bridging hydride at the Fe-Fe bond. In the second part, a model complex with an unprecedented amine ligand was synthesized and studied. In analogy to the enzyme active site, the labile amine ligand is expelled after electrochemical reduction. The third part describes a series of model complexes with electronically different aromatic dithiolate ligands. It is demonstrated in one case that the tuning of the ligand by electron-withdrawing substituents results in proton reduction catalysis at an overpotential that is lower than that required by the non-substituted parent compound. The design and the synthetic work towards a new ruthenium-diiron dyad for light-driven hydrogen production are presented in the fourth part. In the final part, differently isotope-labelled mixed valent Fe(I)-Fe(II) model complexes were synthesized, in particular the unprecedented 15N labelled analogue, with the aim to provide EPR-spectroscopic references that will allow the elucidation of the nature of the central atom in the dithiolate bridge of the [FeFe] hydrogenase active site.

Thesis (Ph. D.)--Open University. BLDSC no. DXN033657.