[pt] O termo agregopatia é utilizado para definir doenças relacionadas ao dobramento incorreto e consequente agregação patológica de proteínas. A doença de Alzheimer (DA) caracteriza-se pela agregação do peptídeo (beta)-amiloide (A(beta)), enquanto o diabetes mellitus tipo 2 (DMT2) está relacionado ao polipeptídeo amiloide das ilhotas pancreáticas (IAPP). O dobramento defeituoso de proteínas e peptídeos leva à formação de oligômeros solúveis e tóxicos, que eventualmente acarretam morte celular. Além disto, ambas doenças apresentam uma componente endócrina (ou neuroendócrina no caso da DA), devido ao papel da insulina em suas fisiopatologias. Uma vez que a interação entre certos íons metálicos, como cobre(II), e determinados peptídeos é considerada uma das causas agravantes da agregação proteica, busca-se impedir ou atenuar as interações anômalas metalproteína através da utilização de metalóforos hidrazônicos. Estes são compostos com afinidade moderada por biometais, desenvolvidos com o intuito de restaurar a homeostase metálica e reduzir o estresse oxidativo presente nestas doenças. Neste contexto, o presente trabalho descreve o desenvolvimento de dois novos metalóforos cujas estruturas foram inspiradas em moléculas que se ligam a receptores celulares: X1TMP (1-metil-1H-imidazol-2-carboxaldeído 3,4,5- trimetoxibenzoíl hidrazona), baseado na mescalina, que se liga seletivamente à receptores cerebrais, e X1NIC (1-metil-1H-imidazol-2-carboxaldeído nicotinoíl hidrazona), pensado com base na estrutura da nicotina, que apresenta receptores funcionais nas ilhotas pancreáticas e em células (beta). Na primeira parte do trabalho, avaliou-se o potencial metalofórico do X1TMP frente a modelos biofísicos de DA, utilizando o peptídeo A(beta)1-40 e seu fragmento coordenante A(beta)1-16, comparando-o com seu derivado não-substituído X1Benz (1-metil-1H-imidazol2-carboxaldeído benzoíl hidrazona). Os valores de log P calculados e experimentais foram semelhantes para ambos e dentro da faixa ideal e, de maneira geral, todos os parâmetros físico-químicos avaliados estão de acordo com as diretrizes para fármacos orais direcionados ao sistema nervoso central. A partir do método de Job, foi verificado que ambas hidrazonas apresentaram interação com cobre(II) com estequiometria do tipo ML. Os valores aparentes de log K foram de 5,74 mais ou menos 0,15 e 5,87 mais ou menos 0,11 para X1TMP e X1Benz respectivamente, indicando que a presença das metoxilas não influencia na estabilidade do complexo formado. Ambos os compostos foram capazes de diminuir a produção de espécies reativas de oxigênio pelo sistema Cu(A(beta)) sob condições pseudo-fisiológicas, com o X1TMP sendo ligeiramente mais eficaz do que o X1Benz. Além disto, as hidrazonas foram capazes de inibir a agregação de A(beta) em condições equimolares na presença e, surpreendentemente, na ausência de cobre(II). Utilizando a técnica 1H15N HSQC foi possível verificar que o X1Benz interage diretamente com o peptídeo, o que justifica o efeito observado. Por outro lado, a inibição da agregação mediada por cobre pode ocorrer através da formação de um complexo ternário, como evidenciado por experimentos de 1H NMR. Na segunda parte do trabalho, estudou-se o efeito do X1NIC no modelo de DMT2. Entretanto, uma mistura de estereoisômeros geométricos foi obtida durante a síntese, o que direcionou o estudo para comparação desses isômeros, e como ambos interagem com o sistema Cu2+ ‒hIAPP. Uma vez purificados e caracterizados, determinou-se experimentalmente os valores de coeficiente de partição octanol-água respectivamente como 0,62 mais ou menos 0,01 e 0,87 mais ou menos 0,02 para X1NIC-(E) e X1NIC-(Z). Mais uma vez a afinidade aparente ligante-metal foi determinada, com valores de log K = 5,82 mais ou menos 0,16 para o isômero tridentado (E) e 5,04 mais ou menos 0,04 para o isômero bidentado (Z). O fragmento coordenante hIAPP18-22 foi utilizado para avaliar a interação do peptídeo com o cobre(II) e o efeito dos ligantes neste sistema. Através de experimentos de RMN de alto campo, a coordenação do tipo N3O foi confirmada para o peptídeo, evidenciando a histidina como sítio de ancoragem do metal. Ambos os isômeros formaram complexos ternários, embora com estabilidades diferentes, conforme demonstrado tanto por RMN quanto por voltametria cíclica. Por outro lado, a adição de um excesso de X1NIC-(E) se mostrou eficaz na remoção de cobre ligado ao peptídeo, enquanto o mesmo não foi observado para X1NIC-(Z), evidenciando a necessidade de um sítio tridentado para uma boa ação metalofórica por parte destes ligantes. Vale ressaltar que provavelmente os próprios complexos ternários sejam capazes de parcialmente neutralizar os efeitos deletérios relacionados à química redox do metal. O presente trabalho complementa o conhecimento acerca da nova geração de metalóforos hidrazônicos contendo 1-metilimidazol, trazendo novas perspectivas para suas aplicações em futuros trabalhos direcionados tanto para DA quanto para o DMT2. / [en] Both Alzheimer s disease (AD) and type-2 diabetes mellitus (T2DM) are considered metal-enhanced aggregopathies, in which the anomalous interactions between copper(II) and the A(beta) and IAPP peptides, respectively, lead to protein misfolding, aggregation and oxidative stress. In this scenario, our research group proposed the use of 1-methylimidazole-containing N-acylhydrazones as metallophores, aiming to compete with the interaction of this metal ion with amyloidogenic proteins, intervening in the process of aggregation and restoring metal homeostasis. In the present work, two new compounds of this series were proposed, based on the structure of mescaline and nicotine: X1TMP and X1NIC. The first was evaluated in biophysical models of AD using the A(beta)1-40 peptide and its fragment A(beta)1-16 and was compared to its unsubstituted analogue X1Benz. X1NIC, on the other hand, was synthesized separately as its (E) and (Z) isomers, and they were in turn studied using the coordinating hIAPP18-22 fragment in the context of T2DM. X1TMP and X1Benz were both able to lessen the coppermediated production of ROS and prevent A(beta) aggregation in the presence and absence of this metal. The formation of ternary species with different stabilities was clearly demonstrated for the studied compounds in both AD and T2DM systems using different techniques. In the case of T2DM, however, only X1NIC- (E) seemed able to remove copper(II) from hIAPP18-22 at ligand excess conditions, which is consistent with its higher affinity for this ion. It is worth mentioning that all tridentate hydrazones [X1TMP, X1Benz and X1NIC-(E)] presented similar, moderate, apparent affinity constant values, while X1NIC-(Z) had a weaker interaction with copper since it performs as a bidentate ligand. In general, these new compounds demonstrated promising metallophoric activity and proved ability to interfere with the anomalous copper-peptide interactions. It is possible that the ternary species are enough to partially passivate the metal, avoiding deleterious redox cycling effects.

The present thesis deals with different aspects of the chemistry and photo-biology of various ferrocene-conjugated metal complexes, their interaction with double helical DNA, DNA photocleavage and photo-enhanced cytotoxicity in visible light. Phenyl analogues of the active complexes have been synthesized and used for comparison in biological assays. Chapter I provides an introduction to the potential of metal complexes as photochemotherapeutic agents with special reference to organometallic compounds. A brief overview of Photodynamic Therapy (PDT) as a new modality of cancer treatment has been given. Various modes of non-covalent interactions of small molecules with duplex DNA are mentioned. Recent reports on the metal-based photocytotoxic and DNA cleaving agents including photoactivatable organometallic compounds are discussed. The objective of the present investigation is also presented in this chapter. Chapter II presents the synthesis, characterization, structure, DNA binding, DNA photocleavage, photocytotoxicity, mechanism of cell death and cellular localization of ferrocene-conjugated L-methionine reduced Schiff base Cu(II) complexes of phenanthroline bases. To explore the role of the ferrocenyl moiety the phenyl analogues of the ferrocenyl complexes are synthesized and used as controls for comparison purpose. Chapter III deals with the photo-induced DNA cleavage and photo-enhanced cytotoxicity of ferrocene-appended L-tryptophan Cu(II) complexes of heterocyclic bases. The synthesis, characterization, structural comparisons, DNA binding, DNA photocleavage, photocytotoxic activity and cell death mechanism in visible light are discussed in detail. Chapter IV describes the synthesis, characterization and structure of ferrocenylmethyl-L-tyrosine Cu(II) complexes of phenanthroline bases. The complexes are evaluated for DNA binding, DNA photocleavage and photocytotoxic activity in visible light. The cellular localization of the complexes and the mechanism of cell death induced by the complexes are also discussed. Chapter V presents the photocytotoxic effect of ferrocene-conjugated L-amino acid reduced Schiff base Cu(II) complexes of anthracenyl/pyrenyl imidazophenanthroline. The ability of the complexes to bind to double helical DNA and cleave it under photo-illumination conditions is described. Evaluation of the complexes as photochemotherapeutic agents and comparison with currently clinically available drug Photofrin are presented. The mechanism of cancer cell death and cellular localization of the complexes are studied by fluorescence microscopy. Chapter VI describes the synthesis, characterization and photochemotherapeutic efficacy of Cu(II) complexes having ferrocene-appended L-amino acid reduced Schiff base ligands and the naturally occurring polyphenol curcumin. Stabilization of curcumin by complexation to metal for improved photodynamic effect in cancer cells is described with comparison to the parent dye and clinically used drug Photofrin. The mechanism of cell death induced by the copper complexes and their localization in cancer cells are also presented. Finally, the summary of the dissertation and conclusions drawn from the present investigations are presented. The references in the text have been indicated as superscript numbers and compiled at the end of each chapter. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the structurally characterized complexes are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is regretted.

The mining of sulphidic ore to extract metals such as zinc and copper produces huge quantities of waste material. The weathering and oxidation of the waste produces what is commonly known as Acid Mine Drainage (AMD), a dilute sulphuric acid rich in Fe(II) and heavy metals. This thesis serves to summarise five papers reporting how the precipitation of Fe(III) phases can attenuate the contamination of heavy metals by adsorption processes. Schwertmannite (Fe8O8(OH)6SO4) is a common Fe(III) mineral precipitating in AMD environments at pH 3-4. The stability and surface chemistry of this mineral was investigated. It was shown that the stability depended strongly on pH and temperature, an increase in either promoted transformation to goethite (α-FeOOH). Two pH dependent surface species of SO42- were detected with infrared (ATR-FTIR) spectroscopy. The adsorption of Cu(II), Pb(II) and Zn(II) to schwertmannite occurred at lower pH than to goethite, whereas Cd(II) adsorption occurred in a similar pH range on both schwertmannite and goethite. Extended x-ray absorption fine structure (EXAFS) spectroscopy suggests two surface species for Cu(II) and Cd(II) at the schwertmannite surface. Cu(II) adsorbs monodentately and Cd(II) bridging bidentately to adsorbed SO42-. Both metal ions also adsorb in a bridging bidentate mode to the surface hydroxyl groups. At pH 7.5 up to 2.7 μmol Cd(II) m-2 could be adsorbed to schwertmannite, indicating a large adsorption capacity for this mineral. The acid-base properties of two NOM samples were characterised and could be well described as diprotic acids below pH 6. The adsorption of NOM to schwertmannite and goethite was very similar and adsorption occured in a very wide pH range. High concentrations of NOM increased the adsorption of Cu(II) to goethite at low pH whereas a slight decrease was noted at low concentrations of NOM. No effect was detected in the schwertmannite system. The formation of Fe(III) phases from precipitation of AMD was shown to be very pH dependent. At pH 5.5 a mixture of minerals, including schwertmannite, formed whereas at pH 7 only lepidocrocite (γ-FeOOH) formed. The concentration of Zn(II) in AMD could by adsorption/coprecipitation be reduced to environmentally acceptable levels.

Thirteen new dinuclear complexes of ligand 2,6-bis[(N-methylpiperazine-1- yl)methyl]-4-formyl phenol (L1) were prepared. Copper(II) and palladium(II) salts were used for the syntheses. Following compounds were prepared: [Cu2L1(CH3COO)2]ClO4, [Cu2L1(CF3COO)2(ClO4)][Cu2L1(CF3COO)2]ClO4, [Pd2L1(CH3COO)3], [Pd2L1(CF3COO)3], [Pd2L1(Cl)4]. These ones should act as anion receptors. The acetates were exchanged for phenylphosphinates in the case of the complex cation [Cu2L1(CH3COO)2]+ and the structure of [Cu2L1(phPO2H)2]ClO4 was obtained. Geometry of coordination shell of Cu2+ - ions in prepared complexes is tetragonal pyramid. The UV-VIS spectroscopy was used for study of interactions in system of the ligand - metal - anion. Interactions between the ligand and metals in oxidation state 2 were observed as well as interactions between the complex [Cu2L1(CH3COO)2]ClO4 and sodium salts.

The last two decades have seen extensive growth in interest in metal-ion assemblies, especially for building new polynuclear exchange-coupled magnetic systems. However, the concept of designing polynuclear extended structures has still not matured to the level of retro-synthetic approach developed for the organic and pharmacological molecules. Although some progress has been made with secondary building units (SBUs) in metal-organic-frameworks (MOFs), the control seems to be just an illusion when it comes to bridging ligands such as the azide ion. When it is asserted that the azido ligand is versatile in its bridging capabilities, what is actually meant is that it would be difficult to predict or control its bridging properties, or in other words, the azido based polynuclear complexes are difficult to pre-design. However, this kind of serendipity is not always bad news for the chemists. For example, the azido ligand has been shown to mediate magnetic exchanges between paramagnetic metals in a predictable fashion (usually depending upon the bonding geometries). Therefore, it is a well-respected ligand in polynuclear assemblies of paramagnetic ions. Serendipitous assemblies offer new magnetic structures that we may not otherwise even think about synthesizing. Similarly, there are other ligands, such as alkoxido, oximato, carboxylato etc. which also behave like azide. These ligands are very important in the study of magnetic exchanges to develop an understanding of the underlying mechanisms in molecular magnetism. Serendipitous assemblies have also led to systems like single molecule magnets (SMMs), which have enriched the field with potential applications in computing and have also been used for the confirmation of the quantum magnetic properties like tunneling phenomenon, spin decoherence etc. Investigations incorporated in this thesis work led to several novel strategies for using serendipity as an advantage and build unprecedented structural topologies with interesting new molecular-magnetic properties. All the reported complexes were thoroughly analyzed through elemental analysis, spectroscopy, X-ray structure determination (both single crystal & powder diffractions) and variable temperature magnetic susceptibility measurements. In a few suitable cases, model structures obtained from the X-ray structures were also employed to study the magnetic exchange mechanisms through density functional theory (DFT) calculations and simulations. CHAPTER 1 of the thesis presents a general review on the ever-growing field of metal-ion assembly. In particular, the importance of the ‘serendipitous approach’ to build new and interesting metal-ion clusters and polyclusters is highlighted. This chapter also describes the basic concepts of exchange-based molecular magnetism as applied to the metal-ion assemblies. CHAPTER 2 describes the concept of using lower molar proportions of blocking bidentate chelating ligands in the neutral copper(II)-azido systems, which increases the number of coordination sites for the versatile azido bridges to assemble the metal-ions in higher dimensions, based on smaller cluster units. Syntheses, structures and magnetic properties of ten novel complexes are described in this chapter: [Cu3(tmen)2(N3)6]n (1), [Cu4(Me-hmpz)2(N3)8]n (2), [Cu4(men)2(N3)8]n (3), [Cu6(deen)2(N3)12]n (4), [Cu6(aem)2(N3)12]n (5), [Cu6(dmeen)2(H2O)2(N3)12]n (6), [Cu6(N,N'-dmen)2(N3)12]n (7), [Cu6(hmpz)2(N3)12]n (8), Cu5(N,N-dmen)2(N3)10]n (9), and [Cu5(N,N'-dmen)5(N3)10]n (10) [tmen = N,N,N',N'-tetramethylethylenediamine, Me-hmpz = 1-methylhomopiperazine, men = N-methylethylenediamine, deen = N,N'-diethylethylenediamine, aem = 4-(2-aminoethyl)morpholine, dmeen = N,N-dimethyl-N'-ethylethylenediamine, N,N'-dmen = N,N'-dimethylethylenediamine, hmpz = homopiperazine, N,N-dmen = N,N-dimethylethylenediamine]. Most of these complexes have simple oligonuclear basic building units (Scheme 1), such as trinuclear (1), tetranuclear (2, 3) and hexanuclear (4-8), but the overall arrangements of these cluster units in higher dimensions vary widely and serendipitously. For example, the hexanuclear complexes 4-7, although having almost identical basic structures, assemble in three- (4, 5) or two- (6, 7) dimensions with different connectivity among the basic structures. However, complex 9 is made from two different building units (Cu2 and Cu3). Complex 10, although having metal to blocking molar ratio 1:1, presents an unprecedented 1D structure for such complexes. Analysis of the magnetic susceptibility data for complexes 1-9 using theoretical exchange models for fitting is also described. Density functional theory (DFT, B3LYP) was employed to further analyze the experimental magnetic data for complexes 1, 2, 3 and 9 to better understand the magnetic exchange mechanisms in such systems. CHAPTER 3 continues with the same concepts developed in the previous chapter using multidentate neutral and anionic co-ligands. Using lower molar proportions of these multidentate ligands, seven novel complexes have been synthesized (keeping the initial metal to ligand ratio as 2:1): [Cu4(L1)2(N3)8]n (11), [Cu4(L2)2(N3)8]n (12), [Cu4(L3)2(N3)8]n (13), [Cu4(L4)2(N3)8]n (14), [Cu9(L5)4(N3)18]n (15), [Cu4(L6)2(H2O)2(N3)6] (16) and [Cu4(L7)2(N3)6]n (17) [where L1-5 are the condensation products of 2-pyridinecarboxaldehyde and 2-{2-(methylamino)ethyl}pyridine (L1), N,N-diethylethylenediamine (L2), N,N-dimethylethylenediamine (L3), N-methylethylenediamine (L4), N,N,2,2-tetramethylpropanediamine (L5); HL6 and HL7 are the condensation products of 2-hydroxy-3-methoxybenzaldehyde with N,N-diethylethylenediamine (HL6), and N-ethylethylenediamine (HL7)]. The ligand L1 is particularly interesting, as it is a hemiaminal ether (usually considered to be unstable intermediates in the reactions of aldehydes and secondary amines in alcoholic solvents), and was found to be trapped in 11. Although 11-13 have identical tetranuclear basic structures (with the rare simultaneous end-on and end-to-end bridges between two neighbouring metal-ions, Scheme 2) and extend in one-dimension. However, 13 is differently organized from the other two complexes. For 14, the bridging structure among the peripheral copper(II) ions changes to double end-on (Scheme 2), and the resulting structure extends in two dimensions. However, with L5, metal to ligand ratio is 9:4 (under similar conditions and initial molar proportions of the components) in 15, which can be seen as two different fragments: [Cu4(L5)4(N3)6]2+ and [Cu5(N3)12]2- linked alternately to give an overall 1D structure. HL6 and HL7 have one ionisable phenolic group that replaces one azido anion and generates two pockets for the metal atoms. These monoanionic ligands give tetranuclear complexes (16 and 17) with basic structures resembling (Scheme 2) to 11-14. While 17 is 1D in nature, two coordinated water molecules prevent the structure of 16 to grow and results in a discrete cluster. The variable temperature magnetic properties of these complexes were thoroughly analyzed through experimental and theoretical (DFT) studies. CHAPTER 4 reports the use of a pyridyl substituted propanediolate ligand in the assembly of two novel 1D heterometallic complexes: [Mn3Na(L)4(CH3CO2)(MeOH)2](ClO4)2∙3H2O (18) and [Mn3Na(L)4(CH3CH2CO2)(MeOH)2](ClO4)2∙2MeOH∙H2O (19) [LH2 = 2-methyl-2-(2-pyridyl)propane-1,3-diol, Scheme 3]; both featuring octahedral MnIV ions linked alternately to one trigonal prismatic MnII ion and even more interestingly to one trigonal prismatic NaI ion (Scheme 3). The complexes are essentially identical in structure and magnetic behavior, showing a weak ferromagnetic interaction among the neighboring manganese ions. DFT studies on a model complex supports the S = 11/2 ground spin state, deduced from dc and ac susceptibility measurements. CHAPTER 5 illustrates the use of a few dicarboxylates as potential bridging ligands to assemble tri- and hexanuclear MnIII-clusters. With the salicylaldoximate (salox) as the [MnIII3O(salox)3]+, triangle-generating moiety and keeping the reaction conditions (solvent, base, reaction time and crystallization process) identical, four new extended complexes that differ both in their basic and higher dimensional organizations are reported. When 1,3-phenylenediacetate (phda) is used (in EtOH), in the resulting complex [MnIII6O2(salox)6(EtOH)4(phda)]n∙(saloxH2)n∙(2H2O)n (20), a single type of MnIII6 clusters are linked by the dicarboxylate (interestingly the complex crystallizes with uncoordinated saloxH2 molecules). However, when two differently substituted isophthalate linkers (5-iodoisophthalate and 5-azidoisophthalate) are used, two almost identical complexes [MnIII6O2(salox)6(MeOH)5(5-I-isoph)]n∙(3MeOH)n (21) and [MnIII6O2(salox)6(MeOH)4(H2O)(5-N3-isoph)]n∙(4MeOH)n (22) are isolated, with two different types of Mn6 clusters (Scheme 4) linked alternately in one dimension. More interestingly, use of another substituted isophthalate (5-nitroisophthalate) produced a heteronuclear complex [MnIII3NaO(salox)3(MeOH)4(5-NO2-isoph)]n∙(MeOH)n(H2O)n (23) with only MnIII3 triangles as the basic cluster assembled in two dimensions. Temperature and field dependent dc and ac susceptibility measurements show that the complexes 20-22 behave as non-interacting single molecule magnets with ground spin state S = 4. Complex 23 is dominantly antiferromagnetic with a ground spin state S = 2. The magnetic behaviours of these complexes are also supported by theoretical calculations (DFT) on models generated from the crystal structures.

Diferentes complexos de cobre(II), contendo ligantes do tipo base de Schiff e um grupamento imidazólico, com interesse bioinorgânico, catalítico e como novos materiais, foram preparados na forma de sais perclorato, nitrato ou cloreto e caracterizados através de diferentes técnicas espectroscópicas (UV/Vis, IR, EPR, Raman) e espectrometria de massa Tandem (ESI-MS/MS), além de análise elementar, condutividade molar e medidas de propriedades magnéticas. Alguns destes compostos, obtidos como cristais adequados, tiveram suas estruturas determinadas por cristalografia de raios-X. As espécies di- e polinucleares contendo pontes cloreto, mostraram desdobramentos das hiperfinas nos espectros de EPR, relacionados à presença do equilíbrio com a respectiva espécie mononuclear, devido à labilidade dos íons cloretos, dependendo do contra-íon e do tipo de solvente utilizado. Adicionalmente, em solução alcalina, estes compostos estão em equilíbrio com as correspondentes espécies polinucleares, onde os centros de cobre estão ligados através de um ligante imidazolato. Em meio alcalino, estes compostos polinucleares contendo ponte imidazolato foram também isolados e caracterizados por diferentes técnicas espectroscópicas e magnéticas. Através da variação estrutural e também do ligante-ponte foi possível modular o fenômeno da interação magnética entre os íons de cobre em estruturas correlatas di- e polinucleares. Os respectivos parâmetros magnéticos foram obtidos com ajuste das curvas experimentais de XM vs T, correlacionando-se muito bem com a geometria, ângulos e distâncias de ligação entre os íons, quando comparado com outros complexos similares descritos na literatura. Posteriormente, estudaram-se os fatores relacionados com a reatividade de todas essas espécies como catalisadores na oxidação de substratos de interesse (fenóis e aminas), através da variação do tamanho da cavidade nas estruturas cíclicas ou de variações no ligante coordenado ao redor do íon metálico. Vários deles se mostraram bons miméticos de tirosinases e catecol oxidases. Um novo complexo-modelo da citocromo c oxidase (CcO), utilizando a protoporfirina IX condensada ao quelato N,N,-bis[2-(1,2-metilbenzimidazolil)etil]amino e ao resíduo de glicil-L-histidina, foi sintetizado e caracterizado através de diferentes técnicas espectroscópicas, especialmente EPR. A adição de H2O2 ao sistema completamente oxidado, FeIII/CuII, a -55°C, ou o borbulhamento de oxigênio molecular a uma solução do complexo na sua forma reduzida, FeII/CuI, saturada de CO, resultou na formação de adutos com O2, de baixo spin, estáveis a baixas temperaturas. / Different Schiff base copper(II) complexes containing an imidazole ligand were prepared as perchlorate, nitrate and chloride salts, and characterized by different techniques (UV/Vis, IR, EPR, Raman) and tandem mass spectrometry (ESI-MS/MS), besides elemental analysis, conductivity measurements and magnetic properties. Some of these complexes, suitable crystals were isolated, allowing its structure to be determined by X-ray crystallography. Equilibria involving mono- and dinuclear species containing chloro-bridges were monitored in solution by EPR spectra, indicating a significant dependence on the solvent, and the counter-ion. In alkaline solution, deprotonation of the imidazole moiety promotes a self-assembled process, by coordination of the irnidazolate nitrogen atom to a copper(II) center of an adjacent unit, leading to the macrociclic or zig-zag-chain structures. These complexes were isolated and characterized by different spectroscopy techniques and magnetic susceptibility. The use of different bridging ligands and well-designed polydentate ligands afforded correlated structural features and exchange coupling constant in a series of di- e polinuclear copper(II) complexes. The magnetic parameters of these compounds were determined by temperaturedependent magnetic studies XM vs T, showing that the sign and the magnitude of the exchange coupling constant depends of the geometry, angle at the bridge, as well as on the bond length between paramagnetic ions, when compared with other complexes already described in the literature. The catalytic activity of the obtained complexes toward the usual biological oxidant, molecular oxygen, were then compared. Most of the di- and polynuclear compounds showed to be efficient catalysts of the aerobic oxidation of amines and o henolic substrates. Differinvg in some structural features, their tyrosinase-like catalytic activity was verified to be influenced by several factors, including steric hindrance of the ligands, cavity dimensions and accessibility of the oxidant to the catalytic center. A new biomimetic model system of the cytochrome c oxidase (CcO) derived from protohemin-IX and it contains a glycyl-L-histidine methyl ester arm axially binds the iron; the bis(benzimidazole) group acts as copper-coordinating site. has been prepared and characterized by different spectroscopic techniques, including EPR spectroscopy. The H2O2 addiction to the fully oxidised state of the system at -55ºC, or bubbling molecular oxygen into a CO-saturated solution of the reduced FeII/CuI state of the complex, resulted in a low spin oxygenated intermediate.

Submitted by (lucia.rodrigues@ufrpe.br) on 2017-02-16T13:10:45Z No. of bitstreams: 1 Romulo Augusto Lins de Campos.pdf: 5930168 bytes, checksum: 7553330ff526456aa81970434c7c3475 (MD5) / Made available in DSpace on 2017-02-16T13:10:45Z (GMT). No. of bitstreams: 1 Romulo Augusto Lins de Campos.pdf: 5930168 bytes, checksum: 7553330ff526456aa81970434c7c3475 (MD5) Previous issue date: 2011-03-16 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Potentiometric sensors are known for their high sensitivity and selectivity. Such sensors have versatility, low cost and robustness, which ensures their applicability in a wide variety of complex chemical samples. The ion-selective electrodes for polymeric membrane are the best known potentiometric sensors, has by these traits. However, modified carbon paste electrodes have gained prominence due a great advance in their studies. This paper proposes an electrode chemically modified carbon paste for potentiometric determination of copper (II), using a new ionophore lariat-crown ether synthesized from precursor aminopropyl triethoxysilane is a silylating agent known in the literature. Studies were conducted to evaluate the influence of pH on the potential, the best buffer as supporting electrolyte, and the experimental design of mixtures to obtain the best composition of EQMPC. The proposed electrode showed a sensitivity of 38.5 mV/decade of activity with a detection limit of 2.04 x 10-5 mol L-1, and as a supporting electrolyte buffer biftalate/HCl pH = 3.0 proving to be promising for application in the determination of Cu(II). The electrode showed no significant analytical sensitivity to Co(II), Ni(II) and Zn(II) being these their main interferences. / Sensores potenciométricos são conhecidos por sua alta sensibilidade e seletividade. Tais sensores apresentam versatilidade, baixo custo e robustez, o que garante a esses sensores aplicabilidade em uma grande variedade de amostras químicas complexas. Os eletrodos íon-seletivos de membrana polimérica são os sensores potenciométricos mais conhecidos, por possuirem essas características. Contudo, os eletrodos modificados de pasta de carbono têm ganhado forte destaque devido ao avanço em seus estudos. Neste trabalho é proposto um eletrodo quimicamente modificado de pasta de carbono para determinação potenciométrica de cobre (II), utilizando um novo ionóforo lariat-éter coroa sintetizado a partir de precursor aminopropil trietoxisilano que é um agente sililante conhecido na literatura. Foram realizados estudos para avaliar a influência do pH sobre o potencial, o melhor tampão como eletrólito de suporte, além do planejamento experimental de misturas para se obter a melhor composição do EQMPC. O eletrodo proposto apresentou uma sensibilidade de 38,5mV/década de atividade com limite de detecção de 2,04 x 10-5 mol L-1, tendo como eletrólito de suporte um solução-tampão biftalato/HCl pH = 3,0 demonstrando ser promissor para aplicação na determinação de íons Cu(II). O eletrodo não apresentou sensibilidade analítica significativa aos íons Co(II), Ni(II) e Zn(II) sendo esses seus principais interferentes.

Diferentes complexos de cobre(II), contendo ligantes do tipo base de Schiff e um grupamento imidazólico, com interesse bioinorgânico, catalítico e como novos materiais, foram preparados na forma de sais perclorato, nitrato ou cloreto e caracterizados através de diferentes técnicas espectroscópicas (UV/Vis, IR, EPR, Raman) e espectrometria de massa Tandem (ESI-MS/MS), além de análise elementar, condutividade molar e medidas de propriedades magnéticas. Alguns destes compostos, obtidos como cristais adequados, tiveram suas estruturas determinadas por cristalografia de raios-X. As espécies di- e polinucleares contendo pontes cloreto, mostraram desdobramentos das hiperfinas nos espectros de EPR, relacionados à presença do equilíbrio com a respectiva espécie mononuclear, devido à labilidade dos íons cloretos, dependendo do contra-íon e do tipo de solvente utilizado. Adicionalmente, em solução alcalina, estes compostos estão em equilíbrio com as correspondentes espécies polinucleares, onde os centros de cobre estão ligados através de um ligante imidazolato. Em meio alcalino, estes compostos polinucleares contendo ponte imidazolato foram também isolados e caracterizados por diferentes técnicas espectroscópicas e magnéticas. Através da variação estrutural e também do ligante-ponte foi possível modular o fenômeno da interação magnética entre os íons de cobre em estruturas correlatas di- e polinucleares. Os respectivos parâmetros magnéticos foram obtidos com ajuste das curvas experimentais de XM vs T, correlacionando-se muito bem com a geometria, ângulos e distâncias de ligação entre os íons, quando comparado com outros complexos similares descritos na literatura. Posteriormente, estudaram-se os fatores relacionados com a reatividade de todas essas espécies como catalisadores na oxidação de substratos de interesse (fenóis e aminas), através da variação do tamanho da cavidade nas estruturas cíclicas ou de variações no ligante coordenado ao redor do íon metálico. Vários deles se mostraram bons miméticos de tirosinases e catecol oxidases. Um novo complexo-modelo da citocromo c oxidase (CcO), utilizando a protoporfirina IX condensada ao quelato N,N,-bis[2-(1,2-metilbenzimidazolil)etil]amino e ao resíduo de glicil-L-histidina, foi sintetizado e caracterizado através de diferentes técnicas espectroscópicas, especialmente EPR. A adição de H2O2 ao sistema completamente oxidado, FeIII/CuII, a -55°C, ou o borbulhamento de oxigênio molecular a uma solução do complexo na sua forma reduzida, FeII/CuI, saturada de CO, resultou na formação de adutos com O2, de baixo spin, estáveis a baixas temperaturas. / Different Schiff base copper(II) complexes containing an imidazole ligand were prepared as perchlorate, nitrate and chloride salts, and characterized by different techniques (UV/Vis, IR, EPR, Raman) and tandem mass spectrometry (ESI-MS/MS), besides elemental analysis, conductivity measurements and magnetic properties. Some of these complexes, suitable crystals were isolated, allowing its structure to be determined by X-ray crystallography. Equilibria involving mono- and dinuclear species containing chloro-bridges were monitored in solution by EPR spectra, indicating a significant dependence on the solvent, and the counter-ion. In alkaline solution, deprotonation of the imidazole moiety promotes a self-assembled process, by coordination of the irnidazolate nitrogen atom to a copper(II) center of an adjacent unit, leading to the macrociclic or zig-zag-chain structures. These complexes were isolated and characterized by different spectroscopy techniques and magnetic susceptibility. The use of different bridging ligands and well-designed polydentate ligands afforded correlated structural features and exchange coupling constant in a series of di- e polinuclear copper(II) complexes. The magnetic parameters of these compounds were determined by temperaturedependent magnetic studies XM vs T, showing that the sign and the magnitude of the exchange coupling constant depends of the geometry, angle at the bridge, as well as on the bond length between paramagnetic ions, when compared with other complexes already described in the literature. The catalytic activity of the obtained complexes toward the usual biological oxidant, molecular oxygen, were then compared. Most of the di- and polynuclear compounds showed to be efficient catalysts of the aerobic oxidation of amines and o henolic substrates. Differinvg in some structural features, their tyrosinase-like catalytic activity was verified to be influenced by several factors, including steric hindrance of the ligands, cavity dimensions and accessibility of the oxidant to the catalytic center. A new biomimetic model system of the cytochrome c oxidase (CcO) derived from protohemin-IX and it contains a glycyl-L-histidine methyl ester arm axially binds the iron; the bis(benzimidazole) group acts as copper-coordinating site. has been prepared and characterized by different spectroscopic techniques, including EPR spectroscopy. The H2O2 addiction to the fully oxidised state of the system at -55ºC, or bubbling molecular oxygen into a CO-saturated solution of the reduced FeII/CuI state of the complex, resulted in a low spin oxygenated intermediate.

Human African trypanosomiasis (sleeping sickness) is a devastating disease which is endemic in parts of sub-Saharan Africa. It is caused by the protozoan parasite T. brucei, which are transmitted by the bite of infected tsetse flies. Although the disease is fatal if left untreated, there is a lack of safe, effective and affordable drugs available; therefore new drugs are urgently needed. The aim of the work presented in this thesis is to develop novel trypanocidal compounds. It is divided into two parts to reflect the two distinct strategies employed to achieve this aim. The first part focuses on the inhibition of glycophosphoinositol (GPI) anchor synthesis by inhibiting the Zn2+-dependent enzyme, GlcNAc-PI de-N-acetylase. Trypanosomes have a variable surface glycoprotein (VSG) coat, which allows them to evade the human immune system. The GPI anchor attaches the VSG to the cell membrane; therefore inhibiting GPI synthesis should expose the parasite to the immune system. Initially, large substrate analogues were synthesized. These showed weak inhibition of the enzyme. Zinc-binding fragments were screened, and small molecule inhibitors based on salicylhydroxamic acid were then synthesized. These compounds showed modest inhibition, but the excellent ligand efficiency of salicylhydroxamic acid indicates this may be a promising starting point for further inhibitors. The second part details the P2 strategy. The P2 transporter is a nucleoside transporter unique to T. brucei, which concentrates adenosine. The transporter also binds and selectively concentrates compounds that contain benzamidine and diaminotriazine P2 motifs, which can enhance the potency and selectivity of these compounds. The sleeping sickness drugs melarsoprol and pentamidine contain P2 motifs. Compounds comprising a P2 targeting motif, a linker and a trypanocidal moiety were synthesized. Initially, a diaminotriazine P2 motif was attached to a trypanocidal tetrahydroquinoline (THQ) protein farnesyl transferase (PFT) inhibitor, with limited success. The P2 strategy was also applied to a non-selective, trypanocidal, quinol moiety. The quinol moiety was attached to diaminotriazine and benzamidine P2 motifs, and an increase in selectivity for T. brucei over MRC5 cells was observed.

[pt] Foram estudados os sistemas binários de complexos de Cu(II) e Al(III) formados com a fosfocreatina (PCr), o adenosina 5 trifosfato (ATP), a glicina (Gli), a serina (Ser), a tirosina (Tir) e a treonina (Tre) e os sistemas ternários (MLaLb) onde La foi o ATP ou a PCr e o Lb foi um dos quatro aminoácidos. O estudo foi realizado em solução aquosa através da técnica potenciométrica e das técnicas espectroscópicas ultravioleta-visível, Raman, RMN e RPE. As constantes de estabilidade foram determinadas pela potenciometria. Considerando L como um dos aminoácidos, foi observado que todos os complexos CuL são mais estáveis que os complexos AlL correspondentes. Este fato pode ser explicado pela grande afinidade entre o Cu(II) e o grupo amino. Por outro lado, os complexos binários formados com os fosfatos (ATP ou PCr) e o Al(III) apresentaram valores maiores de log b, do que os complexos de Cu(II) correspondentes. Este fato pode ser justificado pela grande afinidade do Al(III) com os átomos de oxigênio dos fosfatos. Pela mesma razão, todos os complexos ternários de Al(III) apresentaram-se mais estáveis do que os de Cu(II) correlacionados. Os valores das constantes de estabilidade dos complexos poderiam ser divididos em dois grupos: o dos complexos binários e o dos complexos ternários, com valores mais altos. Para os complexos de cobre, este comportamento foi confirmado pelo decréscimo dos valores dos comprimentos de onda máximos no espectro de absorção e no aumento no parâmetro Ao à medida que as constantes de estabilidade aumentaram. Os comprimentos de onda máximos dos complexos CuATPLb foram maiores que os dos complexos CuPCrLb, o que indica que o ATP deve coordenar com o Cu(II) através de dois átomos de oxigênio dos fosfatos e a PCr deve coordenar, nos complexos CuPCrLb, através de um átomo de oxigênio e um átomo de nitrogênio. O valor de D log K [log bCuLaLb) - (log bCuLa + log bCuLb)] mostrou que, quando La foi o ATP, os complexos ternários de Cu(II) e de Al(III) foram menos estáveis do que os seus binários respectivos, sugerindo não existir qualquer tipo de interação entre os ligantes. Aplicando o mesmo cálculo para os sistemas de Cu(II) onde La foi a PCr e Lb a serina ou a tirosina, o valor de D log K foi maior do que zero, indicando que estes ligantes favoreceram a formação de complexos ternários mais estáveis, o que pode ser justificado pela interação do grupo OH destes aminoácidos com o grupo livre (carboxilato ou fosfato) da PCr. Para todos os complexos AlPCrLb, onde Lb foi um dos quatro aminoácidos em estudo, os valores das constantes de estabilidade dos ternários foram maiores do que a soma das constantes dos seus binários. Este fato, não pode ser justificado pela interação do grupo OH dos aminoácidos com a PCr, já que a glicina não apresenta este grupo. Provavelmente, a interação ocorre através do oxigênio não coordenado do fosfato da PCr e do hidrogênio do grupo amino do aminoácido. O estudo do sistema Al(III):Ser pela espectroscopia Raman, mostrou que o complexo [Al(Ser)(H2O)4] 2+ é a espécie predominante e a serina atua como ligante bidentado (átomo de N do grupo amino e átomo de oxigênio do carboxilato). Este deve ser o comportamento de todos os complexos de Al(III) com os aminoácidos. / [en] The binary systems of Cu(II) and Al(III) complexes with adenosine triphosphate (ATP), phosphocreatine (PCr), glycine (gly), serine (Ser), tyrosine (Tyr) and threonine (Thr) and the ternary systems where La was ATP or PCr and Lb was one of the four amino acids, were investigated. The study was performed in aqueous solution using potentiometry, ultraviolet visible, Raman, NMR and EPR spectroscopies. The stability constants of the complexes were determined by potentiometry. When L is one of the amino acids, it can be observed that all the CuL complexes are more stable than the correspondent AlL complexes. This can be explained by the greater affinity between the Cu(II) and the amino group. On the other hand, the binary complexes formed by one of the phosphates (ATP or PCr) and Al(III) have greater values of log b than the correspondent complexes of Cu(II). This can be explained by the greater affinity of Al(III) ion to the oxygen atoms of the phosphates. For this same reason, all the ternary complexes of Al(III) are more stable than the Cu(II) ones. The values of the stability constants of the complexes could be divided in two groups: one of the binary complexes and the second of the ternary complexes, with higher values. For the Cu(II) complexes this behavior was confirmed by the decreasing of the maximum wavelength in the absorption spectra and the increasing of the A0 parameter as the stability constants increase. The maximum wavelength of the CuATPLb complexes were greater than those of the CuPCrLb complexes and this means that ATP must be bound to Cu(II) ion through two oxygen atoms of the phosphates, whereas in CuPCrLb complexes, PCr is bound through one oxygen atom and one nitrogen atom and the amino acid is the same. Values of DlogK (logbCuLaLb - (logbCuLa+ logbCuLb) showed that when La was ATP, the ternary complexes of Cu(II) and Al(III) were less stable than the binary ones suggesting that it does not occur any interaction between the ligands in the ternary complexes. When La was PCr, the stability constants of the Cu(II) complexes where Lb was Ser or Tyr were greater. This showed that these ligands favored more stable ternary complexes and this must be due to the interaction of the OH group of these amino acids and the phosphate or carboxylate of PCr. For the AlPCrLb complexes, when Lb was one of the four amino acids, the stability constants of the complexes were greater. This shows that in this case, the interaction cannot be between the OH groups of the amino acid since glycine does not have any OH group. Probably the interaction occur through the non coordinated oxygen of the phosphate of PCr and the hydrogen of the amino group of the aminoacid. The study of the sistem Al(III):Ser by Raman spectroscopy, showed that [Al(Ser)(H2O)4]2+is the predominant species and that Ser acts as bidentate ligand (N atom of the amino group and O atom of the carboxylate). This must be the behavior of all the complexes of Al(III) and the amino acids.