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[pt] Câncer pode ser considerado um conjunto de diversas doenças, que unidas, levam desequilíbrio aos tecidos dos quais se originaram. A gênese do tumor está associada, em geral, as mutações que as células sofrem e se acumulam em seu interior. A célula modificada adquire maior capacidade de proliferação, sofrendo expansão clonal transmitindo seus genes para as células filhas. A proliferação desordenada é capaz de formar uma massa sólida e intrincada de células alteradas dentro do órgão onde o tumor foi originado. Os tratamentos atuais contra o câncer são voltados para o diagnóstico do tipo de câncer, sua localização e gravidade, orientação, a seleção de melhores opções de tratamento e o seu progresso. Na segunda metade da década de 1960, Rosenberg descobriu a atividade antitumoral da cisplatina, motivando a busca por novos agentes anticancerígenos baseados em metais. Apesar disso, poucos medicamentos anticancerígenos inorgânicos se mostraram promissores devido a problemas de toxicidade. Diante desse escopo, derivados N-acilhidrazônicos e complexos de cobre(II) têm sido sugeridos como compostos promissores para atingir esse objetivo. Os complexos de cobre(II) têm sido apresentados na literatura como uma alternativa promissora aos compostos anticancerígenos de platina, uma vez que o cobre é um elemento traço essencial com menor efeito colateral. Nas últimas décadas, muitos compostos de coordenação de cobre(II) que apresentam atividade antitumoral foram relatados como promissores compostos ativos contra células tumorais, alguns deles avançando para testes clínicos, como é o caso das Casiopeínas (marca registrada), apresentando diferentes formas de interação com a célula. Diante disso, nosso grupo de pesquisa possui experiência em complexos de cobre(II) com atividade antitumoral já reportados. Além disso, ligantes N,O-doadores N-acilhidrazônicos livres e coordenados revelaram atividade biológica como agentes anticâncer. Isto motivou o design de uma nova geração de ligantes similares, na tentativa de potencializar a atividade antitumoral. Este trabalho compreende a síntese, obtenção e caracterização completa de ligantes inéditos N-acilhidrazônicos que foram totalmente caracterizados, assim como seus novos complexos de cobre (II) obtidos a partir de três sais de partida diferentes, o estudo da reatividade, propriedades espectroscópicas, eletroquímicas e antiproliferativas de uma nova geração de complexos mono e binucleares de cobre(II) derivados desses ligantes N-acilhidrazônicos. Dos dez complexos sintetizados, seis deles apresentaram reatividade frente à HSA (albumina sérica humana), e três complexos tiveram sua atividade antiproliferativa avaliada, apresentando atividade maior que a cisplatina. / [en] Cancer can be considered a collection of various diseases that collectively lead to an imbalance in the tissues from which they originate. The genesis of tumors is generally associated with mutations that accumulate within cells. The altered cell acquires an increased capacity of proliferation, undergoing clonal expansion and transmitting its genes to daughter cells. Disordered proliferation can form a solid and intricate mass of altered cells within the organ where the tumor originated. Current cancer treatments focus on diagnosing the type of cell, its location and severity, guidance, selecting the best treatment options, and monitoring the progress. In the latter half of the 1960s, Rosenberg discovered the antitumor activity of cisplatin, which spurred the search for new metal-based anticancer agents. Despite this, few inorganic anticancer drugs have shown auspicious due to toxicity issues. In this context, N-acylhydrazones and their copper(II) complexes have been suggested as promising compounds for achieving this objective. Copper(II) complexes have been presented in the literature as an alternative to platinum-based anticancer compounds, given that copper is an essential trace element with fewer side effects. In recent decades, many copper(II) coordination compounds exhibiting antitumor activity have been reported as promising active compounds against tumor cells, with some advancing to clinical trials, such as Casiopeínas (trademark), which interact with cells in various ways. Our research group has experience with copper(II) complexes exhibiting reported antitumor activity. Additionally, N,O-donor N-acylhydrazone ligands, both free and coordinated, have demonstrated biological activity as anticancer agents. This has motivated the design of a new generation of similar ligands to enhance antitumor activity. This work encompasses the synthesis, acquisition, and complete characterization of novel N-acylhydrazone ligands, which were thoroughly characterized, as well as their new copper(II) complexes obtained from three different starting salts. The study includes the reactivity, spectroscopic, electrochemical, and antiproliferative properties of a new generation of mono- and binuclear copper(II) complexes derived from these N-acylhydrazone ligands. Of the ten synthesized complexes, six showed reactivity towards human serum albumin (HSA), and three complexes derived from the ligand containing furan as a substituent had their antiproliferative activity evaluated, exhibiting greater activity than cisplatin.

Photo sensitizers showing visible light induced DNA cleavage activity are of current importance for medicinal applications related to photodynamic therapy (PTD) considering greater skin penetration of light near 700 nm. While organic molecules and complexes of 4d-5d metal ions are extensively studied for their DNA photo-damage properties in UV and visible light, the chemistry of 3D metal complexes showing visible light-induced DNA cleavage activity is relatively unexplored efforts have been made in this thesis work to design new ternary copper (II) complexes having a-amino acids Such copper (II) complexes with tunable coordination geometry could find potential applications in PDT. Ternary Copper (II) complexes containing L-methionine, S-methy1-L-cysteine and phenanthroline bases are prepared and characterized. They display DNA binding and visible light induced DNA cleavage activity. An enhancement of the DNA cleavage activity is observed for analogous ternary copper (II) complexes contained L-lysine with a pendant cationic amine moiety as a photo-induced DNA Cleavage activity using binary and ternary copper (II) complexes of L-arginine and phenanthroline bases. We have observed AT selective DNA binding and visible light –induced DNA cleavage activity. The crescent-shaped bis-arginine Copper (II) complex mimics the natural antiviral antibiotic netropsin. T o investigate the role of the pendant groups of the amino acids, we have explored the DNA binding and DNA cleavage activity of analogues L-glutamine and L-asparagine complexes. We have prepared ternary copper (II) complexes containing two photosensitizers, viz., L-tryptophan (L-trp) and dipyridoquininoxaline/dipyridophenazine to achieve double strand breaks forming linear DNA. Complex [Cu(L-trp)(dppz)(H2O)+ shows a stacking arrangement of the indole and dppz rings giving a separation that fits with the base pair separation of ds-DNA. Photosensitizes in these complexes approach two different complementary stands of the ds-DNA, leading to double strand breaks and formation of linear DNA. Mechanistic studies on the DNA photocleavage reactions reveal the formation of singlet oxygen(1O2)species by a type-II pathway in preference to the hydroxyl radical generation. A process leading to an efficient DNA cleavage activity on visible light irradiation. The observation of sequence selectivity and double strand DNA cleavage on red light exposure by national design of the complexes is significant considering importance of the results in the chemistry of photodynamic therapy of cancer. The results of this dissertation open up new avenues for designing and developing 3d metal-based photosensitizers with potential utility in nulcleic acid chemistry.

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.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2014-08-11T14:46:08Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Dissertacao River Souza Magalhaes.pdf: 1856967 bytes, checksum: 6da8a950fc3e088ddd4b5b2558c23691 (MD5) / Made available in DSpace on 2014-08-11T14:46:08Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Dissertacao River Souza Magalhaes.pdf: 1856967 bytes, checksum: 6da8a950fc3e088ddd4b5b2558c23691 (MD5) Previous issue date: 2011-02-25 / This work presents the synthesis of N-[-(4-methylphenyl)]-thiourea, the ligand N-[N'-(2-hydroxyethyll)-(4-methylphenyl)]-guanidine and the copper II complex. The compounds were characterized by infrared spectroscopy,1H NMR and X-ray diffraction. The results of X-ray shows the mode of ligand coordination to the metal ion, in addition to square planar structure, a connection is observed for the trans chromophore CuN2O2. Conformational studies of the molecule the ligand N-[N'-(2-hydroxyethyl)-(4-methylphenyl)]-guanidine and were performed to compare experimental data with calculated data. the computation of ligand molecule N-[N'-(2-hydroxyethyl)-(4-methylphenyl)]-guanidine shows the small energy difference between the threes tautomers, it is not possible to state firmly the most stable. The 1H NMR data show that the solution is more abundant in the tautomer II and III. Calculations of energy transition states for the reaction path. In addition to the calculations of imaginary for the characterization of transition states. / Este trabalho apresenta a síntese da N-[N'-(2-hidroxietil)-(4-metilfenil)]-tioureia, do ligante N-[N'-(2-hidroxietil)-(4-metilfenil)]-guanidina e do complexo de cobre II [Cu(oib)2]. Os compostos foram caracterizados por espectroscopia de infravermelho, RMN de 1H e difração de raios-X. O resultado de DRX mostra o modo de coordenação do ligante ao íon metálico, além da estrutura quadrado planar, é observado uma ligação trans para o cromóforo CuN2O2. Estudos conformacionais da molécula do ligante N-[N'-(2-hidroxietil)-(4-metilfenil)]-guanidina que foram realizados para confrontar dados experimentais com dados calculados. Os cálculos computacionais da molécula do ligante N-[N'-(2-hidroxietil)-(4-metilfenil)]-guanidina mostra uma pequena diferença de energia entre os três tautômeros, não sendo possível afirmar com firmeza o mais estável. Os dados de RMN 1H mostram que o mais abundante em solução é o tautômero II e o III. Cálculos de energia dos estados de transição para o caminho reacional. Além do cálculo das frequências imaginárias para caracterização dos estados de transição.

Diese Dissertation unter dem Titel Experimentelle Bestimmung der elektronischen Eigenschaften anwendungsrelevanter Grenzflächen organischer Halbleiter mittels Photoelektronenspektroskopie wurde am Leibniz Institut für Festkürper- und Werkstoffforschung (IFW) Dresden am Institut für Festkörperforschung (IFF) unter der Betreuung von Prof. Dr. B. Büchner angefertigt. Zur wissenschaftlichen Untersuchung kamen hierbei zwei Typen anwendungsrelevanter Grenzflächen. Zum einem wurde der Einfluss einer Elektrodenpräparation unter Normalbedingungen mittels ex-situ Reinigungsverfahren im Vergleich zu insitu präparierten Kontakten auf das elektronische Verhalten des organischen Halbleiters Sexithiophen an Grenzflächen zu metallischen Substraten studiert. Als Substratmaterialien kamen hierbei die Metalle Silber, Palladium, Gold und Platin zum Einsatz. In einer zweiten Studie wurden die Grenzflächen der organischen Halbleiter Sexithiophen und Kupfer(II)- Phthalocyanin in Kontakt zu dünnen Filmen des Übergangsmetalloxides La0.7Sr0.3MnO3 untersucht. Auch hier wurde eine vergleichende Untersuchung für ex-situ und in-situ gereinigte La0.7Sr0.3MnO3-Kontakte durchgeführt. Die hierzu verwendeten Filme wurden im IFW Dresden am Institut für Metallische Werkstoffe (IMW) hergestellt. Auch im Rahmen dieser Untersuchungen stand der Einfluss von Sauerstoff auf das elektronische und chemische Verhalten an den Grenzflächen im Vordergrund.

The modern world faces a number of challenges related to energy and the environment. Atmospheric levels of carbon dioxide have now surpassed the 400 ppm mark due to the burning of fossil fuels, yet despite its abundance and potential use as a C1 feedstock for value-added products, there are both thermodynamic and kinetic barriers associated with the strong carbon-oxygen bonds that preclude its widespread deployment in industry. Nuclear energy is an alternative power source that reduces carbon emissions by billions of tonnes each year, but there are widespread concerns regarding the treatment of the radioactive waste that it accrues (of which the main component is uranyl, [UO2]2+). Most of the work presented in this thesis concerns the synthesis of transition-metal complexes, with the aim of directing catalytic reactivity to convert CO2 to useful products. Part of this thesis also concerns the synthesis of uranyl complexes and the study of uranyl reduction chemistry, which is relevant to uranyl remediation and nuclear waste treatment at a fundamental level. Making use of Earth-abundant metals to carry out hydrocarbon oxidation catalysis is a further focus of this work, as the efficient production of oxygenated compounds under mild conditions is of importance to the fine-chemical industry. Chapter 1 reviews important complexes reported in the literature that successfully convert CO2 to useful products through molecular, homogenous electro-catalysis and ring-opening copolymerisation catalysis. Reactions that exemplify a two-electron reduction of uranyl (i.e. uranium(VI) to uranium(IV)) are reviewed, along with uranyl complexes that undergo ligand-centred redox to give ligand-based radicals. The state of the literature on hydrocarbon oxidation catalysis is reviewed in the introduction. The development of multinuclear, macrocyclic complexes and the reactivity of dinuclear Pacman complexes are also presented. Chapter 2 reports the synthesis and characterisation of a new set of Schiff-base macrocycles and acyclic dipyrrin ligands. A number of attempted synthetic routes towards incorporating a dipyrrin coordination compartment in a macro-cyclic setting are discussed. Differences in electronic structures between dipyrromethanes and dipyrromethenes are also examined by theoretical and experimental methods. Chapter 3 introduces the coordination chemistry of these new macrocycles with zinc(II), where the isolation of dinuclear and tetranuclear complexes is demonstrated using different zinc(II) precursors. Tetranuclear zinc-alkyl complexes presented here are shown to be resistant to insertion chemistry with small molecules, but readily form zinc-oxo, -hydroxyl and -alkoxide clusters upon protonolysis with water and alcohols. These molecular clusters display reactivity towards CO2: a zinc-hydroxyl complex precipitates ZnCO3 at high temperature; and zinc-alkoxide complexes have been used to catalyse the copolymerisation reaction between CO2 and cyclohexene oxide to form polycarbonates. Chapter 4 describes the synthesis of late-transition-metal complexes of macrocyclic ligands and dipyrrins, and explores the relationship between macrocycle geometry and electronic structure. Their reactivities towards CO2 are assessed here, using cyclic voltammetry to assess the electro-catalytic activity of a number of the complexes. Chapter 5 reports the oxidation chemistry of hydrocarbon substrates catalysed by copper(II) complexes. High-temperature catalysis occurs with bimetallic copper(II) complexes, and this chapter describes how added FeCl3 acts as a co-catalyst, leading to greater catalyst stability and allowing the catalytic reaction to occur at room temperature. A range of analytical methods have been used to deduce the catalytically active species, and chemical kinetic measurements have been used to deduce a possible reaction mechanism. Chapter 6 reports the synthesis of a uranyl(VI) dipyrrin complex and details characterisation of its electronic structure by theoretical and experimental methods. Theoretical modelling has indicated that the observed two-electron reduction of uranium(VI) to uranium(IV) is facilitated by the dipyrrin ligand, representing a novel uranyl reduction mechanism.

[pt] A Doença de Alzheimer (DA) é uma desordem cerebral degenerativa, sendo progressiva e fatal, a qual se caracteriza por disfunções cognitivas e da memória. Uma observação característica na DA é a presença de depósitos fibrilosos insolúveis do polipeptídeo b-amilóide (Ab), que ocorre predominantemente em duas formas, Ab (1-40) e Ab (1-42). Muitas evidências indicam que as interações de Ab com os íons Cu(II) e Zn(II) podem estar relacionadas aos processos que levam à agregação deste peptídeo, já que aqueles foram encontrados nessas placas. Além disso, o cobre, por suas características eletroativas, pode contribuir para a geração de radicais livres, aumentando, desta maneira, o estresse oxidativo. Assim, a prevenção da agregação e a diminuição do estresse oxidativo são consideradas estratégias terapêuticas em potencial para a doença. Assim, destacam-se os compostos atenuantes na interação metal-proteína (MPACs, em inglês), que estão relacionados com a normalização da repartição e da distribuição de biometais, interrompendo as interações anômalas entre os íons metálicos e o peptídeo Ab. Neste trabalho, foram sintetizados dois potenciais MPACs derivados do agente micobactericida isoniazida: um deles com o fragmento 8-hidroxiquinolina (H2L1) e o outro, HL2, estruturalmente relacionado à melatonina. Disto resultam dois ligantes interessantes, capazes de coordenar íons metálicos de importância biológica através de seus átomos doadores N e O. As interações destes compostos com os biometais cobre e zinco foram estudadas no estado sólido pela síntese e caracterização de quatro novos complexos, dois com o íon Cu(II) (complexos 2 e 4) e dois com o íon Zn(II) (complexos 1 e 3). Estudos potenciométricos em solução (meio água/etanol 30/70 porcento v/v) envolvendo ambos os ligantes foram feitos a fim de se determinar as respectivas constantes de protonação, bem como as constantes de formação dos complexos envolvendo os íons em estudo. Realizou-se, para os dois ligantes, uma análise farmacológica in silico, mostrando que eles são atóxicos e que possuem um elevado DrugScore. Experimentos de RMN realizados com H2L1, o mais solúvel dos ligantes, demonstraram que, embora o composto não interaja diretamente com Ab, ele compete efetivamente com este peptídeo pelos íons Cu(II) e Zn(II). Em testes efetuados com ratos Wistar machos, o composto mostrou não ser tóxico em doses de até 200 mg kg-1. Os níveis de GSH (um indicador de estresse oxidativo) e de metalotioneínas no cérebro das cobaias tratadas com o composto são estatisticamente os mesmos daqueles observados nos animais controle (não injetados). Comportamento similar foi observado para os biometais cobre, zinco e ferro. Dessa forma, tais estudos para H2L1, revelaram que ele pode atuar como um potencial MPAC. / [en] Alzheimer s disease (AD) is a progressive and fatal degenerative brain disorder, characterized by cognitive and memory disorders. A characteristic feature of this disease is the presence of insoluble fibrillary deposits of the b-amyloid polypeptide (Ab), which occurs predominantly in two forms, Ab (1-40) and Ab (1-42). Accumulated evidence indicates that Ab interactions with Cu(II) and Zn(II) may be related to the processes that lead to the aggregation of this peptide, since these ions have been found in these plaques. In addition, copper, due to its electroactive characteristics, may contribute to the generation of free radicals, increasing oxidative stress. Thus, the prevention of the peptide aggregation and reduction of oxidative stress are considered potential therapeutic strategies for the disease. In this context, metal-protein interaction attenuating compounds (MPACs) are highlighted, which are related to the normalization of the allocation and distribution of biometals, interrupting the anomalous interactions between metal ions and the Ab peptide. In this study, two potential MPACs derived from the mycobactericidal agent isoniazid were synthesized: one with the 8-hydroxyquinoline (H2L1) fragment and the other, HL2, structurally related to melatonin. This produced two interesting ligands capable of coordinating metal ions of biological importance through their donor atoms N and O. The interactions of these compounds with biometals copper and zinc were studied in solid state by the synthesis and characterization of four new complexes, two with the Cu(II) ion (complexes 2 and 4) and two with the Zn(II) ion (complexes 1 and 3). In-solution potentiometric studies (water/ethanol 30/70 percent v/v medium) involving both ligands were conducted in order to determine their protonation constants, in addition to the formation constants of the complexes involving the ions under study. Pharmacological in silico analyses were performed for the two ligands and demonstrated that both are non toxic and have a high DrugScore. NMR experiments performed with H2L1, the most soluble of the ligands, demonstrated that, although the compound does not interact directly with Ab, it competes effectively with this peptide for Cu(II) and Zn(II) ions. In experiments carried out with male Wistar rats, the compound was shown to be non-toxic in doses up to 200 mg kg-1. GSH (an indicator of oxidative stress) and metallothionein levels in the brains of the animals treated with the compound are statistically the same as those observed in control animals (not injected). Similar behavior was observed for biometals copper, zinc and iron. Thus, these studies to H2L1 revealed that it can act as a potential MPAC.

[pt] Foram sintetizados 16 complexos de cobre(II) coordenados com seis aminoácidos presentes na placa b-amilóide, que está associada à Doença de Alzheimer - ácido aspártico, ácido glutâmico, metionina, glicina, serina e arginina, outros dois aminoácidos também encontrados no cérebro - cisteína e homocisteína, além da L-carnitina e acetil-L-carnitina que vêm sendo utilizados como suplemento alimentar em pacientes com doenças neurodegenerativas. Nosso objetivo foi verificar a afinidade do cobre(II) com estes aminoácidos, uma vez que o envelhecimento provoca aumento no cérebro tanto das concentrações de íons cobre como dos níveis de todos estes aminoácidos (que são consequência de fragmentações peptídicas). Por esta razão, procurou-se trabalhar in vitro com condições próximas ao meio biológico utilizando apenas água deionizada como solvente. Os complexos obtidos foram caracterizados pelas seguintes técnicas: análise elementar (espectrometria de absorção atômica e CHN), condutimetria, análise termogravimétrica, ressonância paramagnética eletrônica, voltametria cíclica e espectroscopia no infravermelho. Foi possível verificar que, exceto a acetil-L-carnitina, todos se comportam como ligantes bidentados e complexam facilmente ao cobre(II). Ácido aspártico, ácido glutâmico, serina, metionina, glicina e arginina se coordenaram através do átomo de oxigênio do grupo carboxilato e do átomo de nitrogênio do grupo amino, cisteína e homocistéina através do átomo de enxofre e do átomo de nitrogênio do grupo amino, L-caritina através do átomo de oxigênio do grupo carboxilato e do átomo de oxigênio alcoólico e acetil-L-carnitina se coordena monodentadamente através do átomo de oxigênio do grupo carboxilato. / [en] Sixteen complexes of copper(II) with six amino acids that are present in the b-amyloid peptide, which is associated with Alzheimer’s disease - aspartic acid, glutamic acid, methionine, glycine, serine and arginine -, two amino acids also found in the brain - cysteine and homocysteine -, as well as L-carnitine and acetyl-L-carnitine, which have been used as food supplement in patients with neurodegenerative diseases, were studied. Our aim was to determine the affinity of copper(II) with these amino acids, since aging causes an increase in brain concentrations of copper ions as well as in the level of all of these amino acids, as a consequence of peptide fragmentation. For this reason, we decided to do an in vitro study in similar conditions as the biological environment, using only deionized water as solvent. These compounds were characterized through the following techniques: elementary analysis (atomic absorption spectrometry and CHN), conductimetry, thermogravimetric analysis, electron paramagnetic resonance, electrochemical analysis, and infrared spectroscopy. It was possible to verify that, except for acetyl-L-carnitine, all amino acids behaved as bidentate ligands. They all form complexes with copper(II) easily. Aspartic acid, glutamic acid, serine, methionine, glycine and arginine coordinate through the oxygen atom of the a-carboxylate group and the nitrogen atom of the amine group. Cysteine and homocysteine coordinate through the sulfur atom and the nitrogen atom of the amine group, L-Carnitine coordinates through one oxygen atom of the carboxylate group and one oxygen atom of the alcohol group, and acetyl-L -carnitine coordinates through the oxygen atom of the carboxylate group.