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Nature uses inorganic elements for biological processes based on the useful chemistry, abundance, and availability of each metal. Transition metals are critical in the biogeochemical cycling of essential elements and the bioinorganic chemistry of organisms. Hydrolysis-prone metals such as iron and titanium are abundant on Earth but are mostly insoluble in oxic aqueous environments. Nearly every organism requires iron for survival, therefore Nature evolved to stabilize iron from hydrolysis and hydrolytic precipitation through protein and small molecule mechanisms. Like iron, titanium primarily exists as insoluble mineral oxides and is second only to iron as the most abundant transition metal in the Earth’s crust. Despite the reputation as an inert and insoluble metal, titanium can be solubilized and made bioavailable through by chemical and biological weathering. Currently there is no known native role for titanium, however it is quite bioactive. As a stronger Lewis acid, titanium can compete with iron in binding to biomolecules and proteins. It is of interest to investigate the interactions between hydrolysis-prone metals and biological systems, from whole cell organisms to proteins and small molecules. The non-pathogenic bacterium Rhodococcus ruber GIN-1 was isolated for its ability to strongly adhere to titanium dioxide (TiO2) over other metal oxides, providing an opportunity to study the interactions between whole bacterial cells and metal oxides. The GIN-1 strain incorporates Ti(IV) ions into its biomass after adherence to anatase, rutile, and a mixture of the two morphologies. Six metals were quantitated in TiO2-exposed and control (unexposed) cells by inductively coupled plasma optical emission spectroscopy. The exposure to TiO2 caused a significant uptake of titanium with concomitant loss of iron, zinc, and possibly manganese. A collaborative project with the Strongin laboratory at Temple University works to develop stable, biomaterial photocatalysts for environment remediation of toxic inorganic contaminants. Ferritins are a class of proteins that mineralizes and stores iron as a non- toxic ferrihydrite nanoparticle. These proteins can be photoactivated with ultraviolet light to release iron from its core to remediate environmental contaminants. Ferritin can be sensitized with plasmonic gold nanoparticles to extend the photoactivity of the catalyst to the visible spectrum. Work in this thesis highlights the contribution to this collaboration from the Valentine laboratory, included the expression and purification of proteins in E. coli (human H-chain ferritin, human L-chain ferritin, and bacterial DNA protection from starved cells protein), mutation of proteins to improve sensitization of catalyst, and biomineralization with iron and titanium. The trafficking of hydrolysis prone metals is vital for the survival of nearly every organism. Iron transport proteins such as transferrins are studied to understand how nature utilizes a difficult essential metal across the domains of life. Most transferrins have two homologous lobes and are believed to have evolved from a gene duplication of a monolobal transferrin. The ascidian Ciona intestinalis has genes for both a bilobal and monolobal transferrin. Nicatransferrin (nicaTf), the monolobal transferrin from C. intestinalis, is a primitive protein that may provide insight on the evolution of transferrins in higher organisms. It is advantageous to use E. coli expression systems to produce recombinant proteins, however protein misfolding and aggregation can be a concern. To improve expression of nicaTf in E. coli, codon optimization and disulfide bonded protein expression were used. Finally, siderophores are small, high affinity iron-chelating molecules secreted from lower organisms that scavenge iron in iron-limiting conditions. R. ruber GIN-1 and R. ruber DSM 43338 strains both secrete siderophores in artificial seawater media. There are several siderophores identified from Rhodococcus species, however none have been reported from any R. ruber strain. A new siderophore was isolated and preliminary work has been done to purify and characterize the molecule. Understanding the siderophore- metal ion interactions may help elucidate the mechanism of how R. ruber cells obtain titanium from the metal-oxide particles. / Chemistry

Yes / Alfred Werner was awarded the Nobel Prize in Chemistry just over 100 years ago. We recall briefly the era in which he was working, his co-workers, and the equipment he used in his laboratories. His ideas were ground breaking: not only does a metal ion have a primary valency (“hauptvalenz”, now the oxidation state), but also a secondary valency, the coordination number (“nebenvalenz”). At that time some refused to accept this idea, but he realised that his new thinking would open up new areas of research. Indeed it did. We illustrate this for the emerging field of medicinal metal coordination chemistry, the design of metal-based therapeutic and diagnostic agents. The biological activity of metal complexes depends intimately not only on the metal and its oxidation state, but also on the type and number of coordinated ligands, and the coordination geometry. This provides a rich platform in pharmacological space for structural and electronic diversity. It is necessary to control both the thermodynamics (strengths of metal-ligand bonds) and kinetics of ligand substitution reactions to provide complexes with defined mechanisms of action. Outer-sphere interactions can also play a major role in target recognition. Our current interest is focussed especially on relatively inert metal complexes which were very familiar to Werner (RuII, OsII, RhIII, IrIII, PtII, PtIV). / We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RDF 2013-14 to NPEB) the ERC (Grant No. 247450 to PJS), EPSRC (Grant No. EP/F034210/1) and EC COST Action CM1105 for support.

Yes / A range of oxobis(phenyl‐1,3‐butanedione) vanadium(IV) complexes have been successfully synthesized from cheap starting materials and a simple and solvent‐free one‐pot dry‐melt reaction. This direct, straightforward, fast and alternative approach to inorganic synthesis has the potential for a wide range of applications. Analytical studies confirm their successful synthesis, purity and solid‐state coordination, and we report the complexes’ uses as potential drug candidates for the treatment of cancer. After a 24‐hour incubation of A549 lung carcinoma cells with the compounds, they reveal cytotoxicity values 11‐fold greater than cisplatin, and remain non‐toxic towards normal cell types. Additionally, the complexes are stable over a range of physiological pH values and show the potential for interactions with BSA. / University of Bradford. Grant Number: Internal Research Development Fund

Yes / Electron‐deficient half‐sandwich complexes are a class of under‐studied organometallics with demonstrated potential as metallodrug candidates. The present study investigates the effect of two 16‐electron organoruthenium complexes ([( p‐ cym)Ru(benzene‐1,2‐dithiolato)] ( 1 ) and [( p ‐cym)Ru(maleonitriledithiolate)] ( 2 )) on the cell viability of non‐immortalised human lymphocytes from healthy individuals. The genotoxic effects of 1 and 2 in lymphocytes using the Comet and cytokinesis‐block micronucleus assays is also investigated. Gene expression studies were carried out on a panel of genes involved in apoptosis and DNA damage repair response. Results show that the two 16‐electron complexes do not have significant effect on the cell viability of human lymphocytes from healthy individuals. However, an increase in DNA damage is induced by both compounds, presumably through oxidative stress production. / This project was supported by the Royal Society (University Research Fellowship No. UF150295 to NPEB), the University of Bradford (RDF Award), and by the Academy of Medical Sciences/the Wellcome Trust/ the Government Department of Business, Energy and Industrial Strategy/ the British Heart Foundation Springboard Award [SBF003\1170 to NPEB].

There is an urgent need to find novel anticancer therapeutics with different mechanisms of action than platinum-containing drugs, particularly for patients who relapse after having been initially treated with a platinum-containing chemotherapy regimen. This chemoresistance phenomena, along with the serious side effects observed with cisplatin, have led research in Medicinal Inorganic Chemistry to using other precious metals for the design of novel anticancer therapeutics. This work reports on the synthesis and characterisation of a series of organometallic drug candidates based on ruthenium, osmium, rhodium, and iridium, followed by investigation of their cancer-inhibiting properties via in vitro and in vivo studies. The cytotoxicity of these complexes against various human cancer cell lines is presented, as well as preliminary studies on their possible modes of action, determined via gene expression studies, cell cycle and apoptosis analysis, reactive oxygen species detection and mitochondrial-membrane potential assays. In addition, to confirm the surprising absence of in vitro toxicity against normal cells exhibited by some compounds, studies on ex vivo/in vitro isolated human lymphocytes from healthy individuals, have been conducted. One lead molecule has been progressed to in vivo studies in mice and toxicity and efficacy were assessed with a series of assays including determination of the maximum tolerated dose and pharmacodynamic studies. Structural modifications of the lead molecule with water-soluble phosphines were subsequently undertaken, with the aim to improve the stability and solubility of the parent 16-electron specie, and evaluations of the biological activity of these novel complexes are presented.

<p dir="ltr">The intrinsic charge transfer properties of a given system are dictated by their electronic structure. The movement of electrons from electron rich to electron deficient moieties of a system can spur useful photophysical properties that have been utilized in the development of materials science. Such systems take advantage of redox-active ligands, which can actively participate in electron transfer, and have the versatility to function as either electron donors or acceptors in charge transfer processes. One of the most widely used family of ligands in the development of such materials is dithiolene (Dt), which can exists in two redox extremes; reduced ene-1,2-dithiolate(2-) (Dt^2-) and oxidized dithione (Dt⁰). Dt ligands draw inspiration from the molybdenum cofactor (Moco) found in molybdenum containing enzymes that are present in all phyla of life. The Dt^2- and Dt⁰ ligands play contrasting roles in charge transfer, however, characterization of their electronic structure when both are incorporated into a coordination complex is underexplored. Detailed computational and experimental interrogation of such complexes are presented to highlight the importance of molecular and electronic structures on their charge transfer properties. Such complexes containing a Mo core are also relevant towards the comprehension of the electronic structure of Moco. This investigation focuses on the fundamental understanding of the charger transfer properties of metallodithiolene complexes containing both Dt^2- and Dt⁰ ligands, and progress towards the synthesis of the closest Moco analogs.</p>

O manganês (Mn) é um elemento essencial, porém pode ser tóxico em concentrações acima do requerido fisiologicamente. Assim, motivado pelo aumento nos teores desse metal na bacia hidrográfica Alto do Paranapanema (ALPA) e o crescente número de estudos internacionais relacionando desordens neurológicas ao excesso de Mn em águas superficiais, o presente trabalho foi conduzido para avaliar o perfil geoquímico e neurotoxicológico do Mn nos organismos em desenvolvimento em função da especiação química do metal. Desta maneira, no período de agosto/2006 a abril/2007, foram realizadas quatro coletas de amostras de águas superficiais e de sedimentos, nos rios Paranapanema e Itapetininga e no reservatório Jurumirim, localizados na bacia hidrográfica Alto do Paranapanema (ALPA, SP). Os estudos de fracionamento químico demonstraram que na bacia ALPA o Mn ocorre basicamente nos sedimentos (Mn ligado a hidr(óxidos) de Fe e Mn > Mn ligado a carbonatos &#8776; Mn intercambiável &#8776; Mn ligado a silicatos > Mn ligado a matéria orgânica) porém em constante troca com a coluna líquida, onde o Mn ocorre como metal particulado e em menor proporção como metal lábil. Acredita-se que esse padrão de distribuição esteja governado pelas características oxidantes e alcalinas desses sistemas aquáticos. Adicionalmente, foi verificado que a origem do Mn nesses sistemas é de caráter natural, porém com ~ 30 % de riscos ecotoxicológicos. Neste sentido, estudos in vitro (modelos de neurônios) e in vivo (embriões de paulistinha, Danio rerio) com as espécies MnCl2, Mn(II)Cit, Mn(III)Cit, Mn(III)PPi (Cit: Citrato, PPi: Pirofosfato) sugeriram que o Mn(II) é mais tóxico do que o Mn(III). Contudo, independentemente da especiação química, o Mn foi mais tóxico para neurônios glutamatérgicos do cerebelo em diferenciação, e para o paulistinha no período embrio-larval, pós-eclosão (> 72 horas pós-fertilização), no qual foram verificados danos neuromusculares. No entanto, a espécie mais tóxica para embriões expostos por 48 h foi o MnCl2 e por 120 h o Mn(II)Cit, sugerindo que o citrato está mediando essa toxicidade, o que é uma exceção ao &#8220;Free Ion Activity Model&#8221;. Conforme esses resultados foram verificados inibição do metabolismo do lactato e do ascorbato in vitro. Estudos de expressão gênica no paulistinha, mediante RT-PCR qualitativo e quantitativo permitiram verificar alterações no gene mitocondrial mt-co1, que pode ser compensada pela superexpressão do gene hspb11. Esses resultados sugerem que os danos induzidos pelas espécies de Mn devem estar associados à disfunção mitocondrial e do metabolismo energético, seguido da indução de estresse oxi-redutivo, o qual pode ser parcialmente revertido pela administração exógena de lactato e/ou ascorbato, sendo propostos os prováveis mecanismos. A probabilidade de que esses eventos toxicológicos aconteçam em outras espécies, incluindo os seres humanos, é sustentada principalmente pelos estudos tóxico-genômicos, dado que em outras espécies podem ser encontrados ortologos para esses genes, e especialmente para mt-co1, que poderia ser um biomarcador da toxicidade do Mn. Finalmente, sugere-se que os valores de referência de Mn em sedimentos sejam revistos em função das contribuições de frações biodisponíveis, e que esses resultados sejam considerados pelas agências ambientais do Estado em seus programas de avaliação e gerenciamentos de riscos / Manganese (Mn) is an essential element, however it may be toxic in higher than recquired physiological levels. The present work was motivated by the increased levels of this metal in the Alto do Paranapanema (ALPA, São Paulo state) hydrographic basin and to the growing amount of international evidence relating neurological disorders to excess Mn in superficial waters. Therefore, experiments were conducted in order to evaluate Mn both geochemical and neurotoxicological profiles on the developmental stages of aquatic organisms and mammaliam models as a function of metal speciation. During August 2006 to April 2007, four expeditions to ALPA were performed to collect water and sediment samples from rivers Paranapanema and Itapetininga, as well as from Jurumirim reservoir. Chemical fractioning studies showed that Mn occurs mainly in sediments (Mn bound to Fe, Mn (hydr)oxides > Mn bound to carbonates &#8776; Interchangeable Mn &#8776; Mn bound to silicates > Mn bound to organic matter) but in constant exchange with the liquid column, where Mn occurs as particulated metal and, in lesser amounts, as a labile metal. This distribution pattern is thought to be governed by the oxidant and alkaline conditions of this aquatic system. Also, Mn was found to be of natural origin, however posing ~ 30% of ecotoxicological risks. In vitro (neuronal cells) and in vivo (zebrafish, Danio rerio embryos) studies with the species MnCl2, Mn(II)Cit, Mn(III)Cit, Mn(III)PPi (Cit: Citrate, PPi: Pyrophosphate) suggest that Mn(II) is more toxic than Mn(III). However, independently of chemical speciation, Mn was more toxic to cerebellar glutamatergic neurons during differentiation and to zebrafish in the embryo- larval period (> 72 hours pos-fertilization), to which neuromuscular damage was observed. The most toxic species for embryos exposed for 48 h was MnCl2, but in the 120 h exposition experiment Mn(II)Cit was more toxic, suggesting that citrate mediates the toxicity, in an exception to the Free Ion Activity Model. According to these results, it was observed inhibition in the metabolism of lactate and ascorbate in vitro. Gene expression studies of zebrafish were performed by both qualitative and quantitative RT-PCR, displaying changes in the expression of the mithocondrial gene mt-co1 which may be compensated by an overexpression of hspb11 gene. These results suggest that the damage induced by Mn species may be related to mitochondrial and energy metabolism disfunction followed by induction of oxi-reductive stress, which can be partially reverted by the exogenous administration of lactate and/or ascorbate. The putative mechanisms are proposed. The possibility that these toxic events might be important to other species, humans included, is substantiated mainly by the toxicogenomics studies, since ortologs for both genes are widespread. This is especially true to mt-co1, which may be a biomarker for Mn toxicity. Finally, it is suggested that the reference values of Mn in sediments should be revised to accomodate the contributions of bioavailable fractions, and that results should be considered by official environment control agencies during their evaluation and risk management programs

Diferentes complexos de cobre(II) contendo um ligante tridentado do tipo imínico e um grupo imidazol foram preparados, na forma de sais perclorato, e caracterizados através de diferentes técnicas espectroscópicas (UV/Vis, IR, Raman e EPR). Em solução aquosa, estes compostos estão em equilíbrio com as correspondentes espécies dinucleares, onde os centros de cobre estão ligados através de uma ponte imidazolato. Em meio alcalino, estes compostos dinucleares e uma espécie tetranuclear foram também isolados e caracterizados. Medidas espectroscópicas e por eletroforese capilar, a diferentes pHs, permitiram estimar o valor da constante de equilíbrio num dos casos. A atividade catalítica desses complexos frente ao peróxido de hidrogênio e ao oxigênio molecular foi então comparada. A maioria dos compostos dinucleares e o tetranuclear mostraram ser eficientes catalisadores para a oxidação aeróbica de substratos fenólicos, com formação da correspondente difenoquinona, monitorada espectrofotometricamente, exibindo uma dependência de primeira ordem da velocidade de reação com a concentração do fenol e do complexo. Por outro lado, o estudo cinético da decomposição catalítica do peróxido de hidrogênio, monitorada manometricamente através do oxigênio liberado, indicou uma apreciável atividade dos compostos mononucleares, dependendo do pH. Neste caso, espécies reativas de oxigênio foram detectadas por EPR, utilizando o método do captador de spin. Parâmetros espectroscópicos e características estruturais destes complexos mostraram ser determinantes para sua reatividade frente a ambos os oxidantes biológicos estudados. / Different copper(II) complexes containing an imidazole ligand, in addition to a discrete tridentate imine, were prepared as perchlorate salts, and characterized by spectroscopic techniques (UV/Vis, IR, Raman and EPR). In aqueous solution, these compounds are in equilibrium with the corresponding binuclear species, where the copper centres are bridged by an imidazolate ligand. In alkaline solutions, these binuclear species and a tetranuclear were also isolated, and characterised. Evidence of these equilibria in aqueous solution was obtained by spectroscopic measurements and capillary electrophoresis, at different pH. An equilibrium constant involving the mono- and binuclear species was estimated for one of the ligands. The catalytic activity of the obtained complexes toward the usual biological oxidants, hydrogen peroxide and molecular oxygen, were then compared. Most of the binuclear and tetranuclear compounds showed to be efficient catalysts of the aerobic oxidation of phenolic substrates to the corresponding quinones or diphenoquinones, followed spectrophotometrically. Kinetic results indicated a first-order dependence of the reaction rate on both the complex and the phenol concentrations. On the other hand, an appreciable activity of the mononuclear compounds was verified on the catalytic decomposition of hydrogen peroxide. This reaction was monitored manometrically by the oxygen released, and was shown to be very dependent on the pH. Additionally, in this case, very reactive oxygen radicals were detected at the first stages of the reaction, by spin trapping EPR. Spectroscopic parameters and structural features in these complexes seem to be determinant of their reactivity toward the studied biological oxidants.

Diferentes complexos de cobre(II) contendo um ligante tridentado do tipo imínico e um grupo imidazol foram preparados, na forma de sais perclorato, e caracterizados através de diferentes técnicas espectroscópicas (UV/Vis, IR, Raman e EPR). Em solução aquosa, estes compostos estão em equilíbrio com as correspondentes espécies dinucleares, onde os centros de cobre estão ligados através de uma ponte imidazolato. Em meio alcalino, estes compostos dinucleares e uma espécie tetranuclear foram também isolados e caracterizados. Medidas espectroscópicas e por eletroforese capilar, a diferentes pHs, permitiram estimar o valor da constante de equilíbrio num dos casos. A atividade catalítica desses complexos frente ao peróxido de hidrogênio e ao oxigênio molecular foi então comparada. A maioria dos compostos dinucleares e o tetranuclear mostraram ser eficientes catalisadores para a oxidação aeróbica de substratos fenólicos, com formação da correspondente difenoquinona, monitorada espectrofotometricamente, exibindo uma dependência de primeira ordem da velocidade de reação com a concentração do fenol e do complexo. Por outro lado, o estudo cinético da decomposição catalítica do peróxido de hidrogênio, monitorada manometricamente através do oxigênio liberado, indicou uma apreciável atividade dos compostos mononucleares, dependendo do pH. Neste caso, espécies reativas de oxigênio foram detectadas por EPR, utilizando o método do captador de spin. Parâmetros espectroscópicos e características estruturais destes complexos mostraram ser determinantes para sua reatividade frente a ambos os oxidantes biológicos estudados. / Different copper(II) complexes containing an imidazole ligand, in addition to a discrete tridentate imine, were prepared as perchlorate salts, and characterized by spectroscopic techniques (UV/Vis, IR, Raman and EPR). In aqueous solution, these compounds are in equilibrium with the corresponding binuclear species, where the copper centres are bridged by an imidazolate ligand. In alkaline solutions, these binuclear species and a tetranuclear were also isolated, and characterised. Evidence of these equilibria in aqueous solution was obtained by spectroscopic measurements and capillary electrophoresis, at different pH. An equilibrium constant involving the mono- and binuclear species was estimated for one of the ligands. The catalytic activity of the obtained complexes toward the usual biological oxidants, hydrogen peroxide and molecular oxygen, were then compared. Most of the binuclear and tetranuclear compounds showed to be efficient catalysts of the aerobic oxidation of phenolic substrates to the corresponding quinones or diphenoquinones, followed spectrophotometrically. Kinetic results indicated a first-order dependence of the reaction rate on both the complex and the phenol concentrations. On the other hand, an appreciable activity of the mononuclear compounds was verified on the catalytic decomposition of hydrogen peroxide. This reaction was monitored manometrically by the oxygen released, and was shown to be very dependent on the pH. Additionally, in this case, very reactive oxygen radicals were detected at the first stages of the reaction, by spin trapping EPR. Spectroscopic parameters and structural features in these complexes seem to be determinant of their reactivity toward the studied biological oxidants.