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Sulfonamidas e seus diferentes derivados são extensivamente utilizados na medicina devido a suas propriedades farmacológicas, tal como sua atividade antibacteriana. Propriedades toxicológicas e farmacológicas modificadas vêm sendo observadas quando essas sulfonamidas são administradas nas formas de complexos metálicos. Neste trabalho, utilizamos as moléculas sulfadimetoxina (4-p-aminobenzenosulfonamida-2,6-dimetoxipirimidina) e sulfisoxazol (N(1)-(3,4-dimetil-5-isoxazolil)sulfanilamida) complexados com Cu(II) para acessar seus mecanismos de interação com modelos de membranas lipídicas. Foram feitos experimentos de calorimetria diferencial de varredura (DSC) e de ressonância paramagnética eletrônica (RPE) em soluções contendo os complexos de cobre na presença de modelos de membranas biológicas compostos por fosfolipídios e, no caso de RPE, contendo sondas magneticamente ativas. Amostras foram preparadas utilizando-se o fosfolipídio dipalmitoilfosfatidilcolina (DPPC) e, para os experimentos de RPE, contendo também derivados de DPPC marcados com sonda magnética disposta ao longo da cadeia acila (n-PCSL, onde n=5, 12 e 16). Os resultados de DSC mostram que ambos os complexos alteram tanto a transição de fase principal quanto a pré-transição dos fosfolipídios componentes do modelo de membrana, indicando assim a existência de interação e de maior desordenamento da membrana na presença dos complexos de cobre. Os espectros de RPE mostram que os complexos de cobre afetam, principalmente, a fase gel dos fosfolipídios e maiores alterações são percebidas em posições da membrana mais próximas à interface membrana-solvente. Nossos dados indicam que interações não-específicas entre os complexos de cobre e membranas podem ser um mecanismo utilizados pelo fármaco para vencer as barreiras físicas da célula. / Sulfonamides and their different derivatives are extensively used in Medicine due to their pharmacological properties, such as antibacterial activity. Modified toxicological properties have been observed when those sulfonamides are administered in the form of metal complexes. In this work, we used the molecules sulfadimethoxine (4-p-aminobenzenesulfonamido-2,6-dimethoxypyrimidine) and sulfisoxazole (N (1) - (3,4-dimethyl-5-isoxazolyl) sulfanilamide) complexes with Cu(II) to assess their mechanism of interaction with lipid model membranes. Differential Scanning Calorimetry (DSC) and Electron Paramagnetic Resonance (EPR) experiments were carried out to monitor the influence of the complexes on the lipid thermotropic behavior. Samples consisting of the multilamellar vesicles of dipalmitoylphosphatidylcholine (DDPC) and, in the case of EPR, spin labeled phospholipids were used as models for the membrane. DSC results showed that the presence of the complexes affects both the pre-transition and the main phase transition of the lipids in the membrane. A disordering effect is evidenced by the decrease in Tm and Tp values. ESR results showed that the major alterations are detected in the lipid gel phase and for the labels positioned close to the lipid-water interface. Overall our results indicate that non-specific interactions between the complexes and the membrane might be a mechanism used by the drugs to overcome the physical barriers found in the cell.

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.

Sulfonamidas e seus diferentes derivados são extensivamente utilizados na medicina devido a suas propriedades farmacológicas, tal como sua atividade antibacteriana. Propriedades toxicológicas e farmacológicas modificadas vêm sendo observadas quando essas sulfonamidas são administradas nas formas de complexos metálicos. Neste trabalho, utilizamos as moléculas sulfadimetoxina (4-p-aminobenzenosulfonamida-2,6-dimetoxipirimidina) e sulfisoxazol (N(1)-(3,4-dimetil-5-isoxazolil)sulfanilamida) complexados com Cu(II) para acessar seus mecanismos de interação com modelos de membranas lipídicas. Foram feitos experimentos de calorimetria diferencial de varredura (DSC) e de ressonância paramagnética eletrônica (RPE) em soluções contendo os complexos de cobre na presença de modelos de membranas biológicas compostos por fosfolipídios e, no caso de RPE, contendo sondas magneticamente ativas. Amostras foram preparadas utilizando-se o fosfolipídio dipalmitoilfosfatidilcolina (DPPC) e, para os experimentos de RPE, contendo também derivados de DPPC marcados com sonda magnética disposta ao longo da cadeia acila (n-PCSL, onde n=5, 12 e 16). Os resultados de DSC mostram que ambos os complexos alteram tanto a transição de fase principal quanto a pré-transição dos fosfolipídios componentes do modelo de membrana, indicando assim a existência de interação e de maior desordenamento da membrana na presença dos complexos de cobre. Os espectros de RPE mostram que os complexos de cobre afetam, principalmente, a fase gel dos fosfolipídios e maiores alterações são percebidas em posições da membrana mais próximas à interface membrana-solvente. Nossos dados indicam que interações não-específicas entre os complexos de cobre e membranas podem ser um mecanismo utilizados pelo fármaco para vencer as barreiras físicas da célula. / Sulfonamides and their different derivatives are extensively used in Medicine due to their pharmacological properties, such as antibacterial activity. Modified toxicological properties have been observed when those sulfonamides are administered in the form of metal complexes. In this work, we used the molecules sulfadimethoxine (4-p-aminobenzenesulfonamido-2,6-dimethoxypyrimidine) and sulfisoxazole (N (1) - (3,4-dimethyl-5-isoxazolyl) sulfanilamide) complexes with Cu(II) to assess their mechanism of interaction with lipid model membranes. Differential Scanning Calorimetry (DSC) and Electron Paramagnetic Resonance (EPR) experiments were carried out to monitor the influence of the complexes on the lipid thermotropic behavior. Samples consisting of the multilamellar vesicles of dipalmitoylphosphatidylcholine (DDPC) and, in the case of EPR, spin labeled phospholipids were used as models for the membrane. DSC results showed that the presence of the complexes affects both the pre-transition and the main phase transition of the lipids in the membrane. A disordering effect is evidenced by the decrease in Tm and Tp values. ESR results showed that the major alterations are detected in the lipid gel phase and for the labels positioned close to the lipid-water interface. Overall our results indicate that non-specific interactions between the complexes and the membrane might be a mechanism used by the drugs to overcome the physical barriers found in the cell.

Nesta dissertação, apresentamos dois estudos por ressonância paramagnética eletrônica (RPE) de complexos de cobre. O primeiro estudo contempla os complexos mononucleares de cobre e seu objetivo é analisar a simetria de coordenação dos sítios paramagnéticos. Os espectros de RPE obtidos em banda X na temperatura de 50K para as amostras de membranas e bio-membranas dopadas com Cu(ClO4)2 indicam a presença do íon Cu2+ em sítios de simetria axial. Com a análise dos espectros experimentais, obtivemos os parâmetros do Hamiltoniano de spin e através do modelo empírico de Peisach-Blumberg foi possível observarmos que, para a maioria das amostras analisadas, a complexação equatorial do íon Cu2+ ocorre com átomos de nitrogênio e oxigênio. O segundo estudo contempla os complexos dinucleares de cobre e seu objetivo é analisar as interações dipolar e de troca. Os espectros obtidos em banda Q em temperatura ambiente (300K) para o complexo dinuclear [Cu2(Sant)4 (H2O)2] 2.5H2O em sua forma monocristalina indicaram a presença do íon Cu2+ em sítios de simetria axial com duas unidades dinucleares magneticamente não equivalentes por célula unitária na amostra. Com a análise da variação angular das linhas de ressonância foi possível obtermos os parâmetros do Hamiltoniano de Spin e estimarmos a constante de acoplamento de troca como sendo J0 <&asymp;>324 cm1. / This dissertation presents two electron paramagnetic resonance (EPR) studies on copper complexes. The first study focused mononuclear copper complexes and its objective is to analyze the symmetry of coordination of the paramagnetic sites. The 50K X-band EPR spectra obtained for membranes and bio-membranes doped with Cu(ClO4)2 indicates the presence of the Cu2+ ion in axially distorted sites. Through the analysis of the experimental spectra the spin Hamiltonian parameters are obtained and using the Peisach-Blumberg empirical model its possible to notice that the equatorial complexation of the Cu2+ ion occurs with both nitrogen and oxigen for most of the samples. The second study focused dinuclear copper complexes and its objective is to analyze both dipolar and exchange interactions. The room temperature Q-band EPR spectra obtained for the monocrystalline form of the dinuclear complex [Cu2(sant)4 (H2O)2] 2.5H2O indicates the presence of the Cu2+ ion in axially distorted sites with two non-equivalent dimeric units per unit cell of the sample. With the analisys of the angular variation of the resonant lines we are able to obtain the spin Hamiltonian parameters and estimate the exchange coupling constant J0 &asymp; 324 cm1.

Nesta dissertação, apresentamos dois estudos por ressonância paramagnética eletrônica (RPE) de complexos de cobre. O primeiro estudo contempla os complexos mononucleares de cobre e seu objetivo é analisar a simetria de coordenação dos sítios paramagnéticos. Os espectros de RPE obtidos em banda X na temperatura de 50K para as amostras de membranas e bio-membranas dopadas com Cu(ClO4)2 indicam a presença do íon Cu2+ em sítios de simetria axial. Com a análise dos espectros experimentais, obtivemos os parâmetros do Hamiltoniano de spin e através do modelo empírico de Peisach-Blumberg foi possível observarmos que, para a maioria das amostras analisadas, a complexação equatorial do íon Cu2+ ocorre com átomos de nitrogênio e oxigênio. O segundo estudo contempla os complexos dinucleares de cobre e seu objetivo é analisar as interações dipolar e de troca. Os espectros obtidos em banda Q em temperatura ambiente (300K) para o complexo dinuclear [Cu2(Sant)4 (H2O)2] 2.5H2O em sua forma monocristalina indicaram a presença do íon Cu2+ em sítios de simetria axial com duas unidades dinucleares magneticamente não equivalentes por célula unitária na amostra. Com a análise da variação angular das linhas de ressonância foi possível obtermos os parâmetros do Hamiltoniano de Spin e estimarmos a constante de acoplamento de troca como sendo J0 <&asymp;>324 cm1. / This dissertation presents two electron paramagnetic resonance (EPR) studies on copper complexes. The first study focused mononuclear copper complexes and its objective is to analyze the symmetry of coordination of the paramagnetic sites. The 50K X-band EPR spectra obtained for membranes and bio-membranes doped with Cu(ClO4)2 indicates the presence of the Cu2+ ion in axially distorted sites. Through the analysis of the experimental spectra the spin Hamiltonian parameters are obtained and using the Peisach-Blumberg empirical model its possible to notice that the equatorial complexation of the Cu2+ ion occurs with both nitrogen and oxigen for most of the samples. The second study focused dinuclear copper complexes and its objective is to analyze both dipolar and exchange interactions. The room temperature Q-band EPR spectra obtained for the monocrystalline form of the dinuclear complex [Cu2(sant)4 (H2O)2] 2.5H2O indicates the presence of the Cu2+ ion in axially distorted sites with two non-equivalent dimeric units per unit cell of the sample. With the analisys of the angular variation of the resonant lines we are able to obtain the spin Hamiltonian parameters and estimate the exchange coupling constant J0 &asymp; 324 cm1.

Thesis (MSc (Chemistry and Polymer Science))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: In this thesis we describe the synthesis of several new N-(n-propyl)-1-(2-pyridyl and quinolyl)-imine ligands (ML1-ML4) as well as peripheral functionalised iminopyridyl and iminoquinolyl poly(propylene-imine) dendrimeric ligands (DL1-DL8) with a 1,4- diaminobutane core. The dendrimeric ligands were obtained by modification of the peripheral groups of Generation 1 and Generation 2 poly(propylene-imine) dendrimers, (DAB-(NH2)n which are commercially available, with a series of aldehydes. All the ligands were fully characterised by ESI-mass spectrometry, elemental analysis, 1H&13C{1H}-NMR, FT-IR and UV/Vis spectroscopies. These ligands were utilised to synthesise Pd(II) and Cu(I) complexes using appropriate metal precursors. Some of mononuclear complexes, [N-(n-propyl)-(2-pyridyl and quinolyl) methanimine] dichloro Pd(II) complexes (C1-C4) and bis[N-(n-propyl)-(2-pyridyl and quinolyl) methanimine] copper(I) tetrafluoroborate complexes (C14) were structurally characterised. Pd(II) complexes adopted a distorted square-planar geometry around the metal centre while Cu(I) complex exhibit a distorted tetrahedral arrangement around the metal centre. Both Pd(II) and Cu(I) multinuclear complexes (metallodendrimers) were characterised using a range of analytical techniques. / AFRIKAANSE OPSOMMING: In hierdie tesis word die sintese van verskeie nuwe N-(n-propiel)-1-(2-piridiel) en kinolielimien ligande (ML1-ML4) sowel as gefunksioneerde imienopiridiel en imienokinoliel poli(propilien-imien) dendrimeriese ligande (DL1-DL8) beskryf. Die dendrimeriese ligande was behaal deur die modifikasie van perifere groepe van Generasie 1 en Generasie 2 poli(propilien-imien) dendrimere met ‘n reeks aldehiede. Alle ligande was volledig deur ESI-massaspektrometrie, elementele analiese, 1H en 13C{1H} – KMR, FT-IR en UV/Sigbare spektroskopie gekarakteriseerd. Hierdie ligande was gebruik om Pd(II) en Cu(I) komplekse te berei om van die gepaste metaal voorlopers te gebruik te maak. Sommige van die mono-kern komplekse, [N-(npropiel)-( 2-piridiel) en kinoliel metanimien] dikloor Pd(II), komplekse (C1-C4) en bis[N-(npropiel)-( 2-piridiel) metanimien] koper(I) tetrafloorboraat, kompleks (C14) was struktureël gekarakteriseerd. Pd(II) komplekse neem ‘n versteurde vierkant valk geometrie om die metaal senter aan, terwyl die Cu(I) kompleks, ‘n versteurde tetrahedriese opset rondom die metaal toon. Beide Pd(II) en Cu(I) multikern komplekse (metaaldendrimere) was deur ‘n verskeidenheid van analitiese tegnieke gekarakteriseerd.

In this thesis, the paper is divided into 2 parts, each corresponding to 2 individual projects. We started with looking into the synthesis of 3-coordinate palladium complexes incorporating a nacnac ligated system for academic interest. We utilized [{2,6-iPr2Ph)2nacnac}PdCl]2 as the precursor into synthesizing these 3-coordinate palladium complexes. Through many failed attempts of manipulating different substrates, we were able to synthesize a 4-coordinate [{(2,6-iPr2Ph)2nacnacPdCl}(NH2Ph)]. The second project deals with the application of dibromobis(1,1'-dibenzyl-3,3'-methylenediimidazolin-2,2'-diylidene)dicopper(I) complex to catalysis. We decided to focus our attentions specifically on carbonyl reduction of ketones being that hydrosilations with copper catalysts have only been recently looked at. The dibromobis(1,1'-dibenzyl-3,3'-methylenediimidazolin-2,2'-diylidene)dicopper(I) complex proved to be very effective at hydrosilations of a wide variety of ketones at high temperatures. We further investigated the scope of the dibromobis(1,1'-dibenzyl-3,3'-methylenediimidazolin-2,2'-diylidene)dicopper(I) catalyst by testing it on the arylation and alkylation of imidazole. The arylation of imidazole showed little to no conversion, whereas the alkylation proved to be quite active for both alkyl bromides and chlorides. We also looked at the attempts in synthesizing bulkier analogues of dibromobis(1,1'-dibenzyl-3,3'-methylenediimidazolin-2,2'-diylidene)dicopper(I) by varying the benzyl groups to 2,6-diisopropylphenyl and mesityl groups. However, results show that there were difficulties in coordinating these bulkier ligands onto copper. Optimization of complexing bulkier ligands onto copper needs to be conducted before one can proceed onto further reactions.

Neste trabalho foram sintetizados complexos de cobre(II) com derivados imínicos da isatina, incluindo isatinas bromadas semelhantes a compostos encontrados em gastrópodes, a fim de compará-los com o composto já produzido e investigado [Cu(isaepy)], complexo de cobre(II) com base de Schiff feita a partir da isatina e 2-aminoetilpiridina. A isatina é um oxindol produzido em algumas plantas, também encontrado no tecido de mamíferos, com propriedades antitumorais naturais. Isatinas bromadas foram previamente constatadas como mais citotóxicas frente a células tumorais do que a isatina sem substituições. O objetivo principal foi verificar se a presença de bromo nos compostos análogos ao [Cu(isaepy)] levaria a um aumento da atividade antitumoral, assim como maior interação com DNA, alvo usual de metalofármacos. Depois de sintetizados, os compostos foram caracterizados por análise elementar (CHN), espectroscopia no infravermelho, espectroscopia UV/Vis e EPR. Foram feitos testes de citotoxicidade pelo método MTT com células de sarcoma uterino (MES-SA e MES-AS/Dx5, esta última resistente a doxorrubicina), adenocarcinoma cervical (HeLa) e células não cancerosas de fibroblasto humano P4. Adicionalmente, foram feitos testes de interação com DNA por UV/Vis e dicroísmo circular, além de testes de clivagem de DNA plasmidial. De modo geral, foi demonstrado que a simetria tetragonal em torno do cobre, determinada pelo EPR, é importante para a citotoxicidade dos complexos, que dessa forma podem se intercalar ao DNA e impedir sua replicação, por acabar distorcendo a hélice, e pela habilidade de realizarem clivagem oxidativa das fitas. [Cu(isaepy)] e seus análogos bromados demonstraram uma atividade citotóxica muito parecida, assim como grau de interação e clivagem com DNA. Conclui-se que, embora a presença de bromo nos análogos de [Cu(isaepy)] não levem a um aumento de atividade antitumoral, como observado em ligantes correlatos livres, nossos estudos apontam para diferentes fontes naturais (animal ou vegetal) para obtenção de precursores de novos compostos antitumorais. / In the present work, copper(II) complexes were synthesized with isatin derived imine ligands, including brominated oxindoles similar to compounds found in gastropods, in order to compare their reactivity with that of [Cu(isaepy)], a Schiff base-copper(II) complex already investigated, obtained with the precursors isatin and 2-aminoethylpyridine. Isatin is a natural oxindole extracted from plants, and also found in mammal tissue, with antitumor properties. Brominated isatins were previously described as much more cytotoxic, towards tumor cells, than unsubstituted isatin. The aim of this work was to verify if the presence of brome in analogue [Cu(isaepy)] compounds would increase their antitumor activity, along with higher DNA interaction, an usual target for metallodrugs. The copper(II) complexes were synthesized and then characterized through elemental analyses (CHN), infrared, UV/Vis and EPR spectroscopies. Cytotoxicity tests were carried out using MTT assay with cells lines MES-SA e MES-SA/Dx5 (uterine sarcome, sensitive and resistent to doxorubicin), HeLa (cervical adenocarcinoma) and non-tumor cells, human fibroblast P4. Additionally, DNA interaction experiments were carried out through UV/Vis spectroscopy and circular dichroism, and at last, DNA cleavage experiments with the studied complexes. In general, it was shown that a tetragonal symmetry around copper, shown by EPR, is very important to the complexes toxicity, since in that way they are able to intercalate DNA, and prevent its replication, as a consequence of double helix distortion, and eventual oxidative cleavage. [Cu(isaepy)] and its brominated analogues demonstrated a very similar cytotoxicity towards cancer cells, as well as quite same level of DNA interaction and cleavage. Although the presence of brome did not increase significantly their antitumor activity, as verified with the free isatin derivatives, our studies pointed to different natural sources to obtain precursors for such new antitumor compounds.

Neste trabalho estudamos propriedades estruturais, magnéticas e eletrônicas de complexos de cobre em duas classes de ligantes semelhantes com potenciais aplicações nas áreas de nanotecnologia e farmacologia. A primeira classe de ligantes é do tipo bases de Schiff, conhecidas por sua vasta gama de aplicações em química e biologia, aqui estudadas como miméticos de sítios de proteínas e também como potenciais metalo-fármacos. Procuramos investigar as características estruturais e eletrônicas buscando correlacionar as informações obtidas experimentalmente com as obtidas através de cálculos de estrutura eletrônica. Em especial, no estudo da competição pelo íon Cu entre as bases de Schiff e a proteína albumina, mostramos a influência de diversos fatores como, por exemplo, a geometria dos ligantes e a sua estrutura eletrônica. A segunda classe estudada é constituída de bases modificadas de DNA com a habilidade de complexar metais (espécie [M-DNA]) e formar estruturas com acoplamento ferromagnético. Observamos para as espécies [M-DNA] que o acoplamento ferromagnético é estabilizado através de dois efeitos: a) diferentes estados de carga que podem gerar distorções na coordenação quadrado planar; b) a adição do backbone do DNA. Utilizamos neste estudo o método Projector Augmented Wave (PAW) e também bases locais dentro da Teoria do Funcional da Densidade, atrav´es dos c´odigos computacionais CP-PAW e Gaussian03. / We studied structural, electronic and magnetic properties of copper complexes with two similar classes of ligands with potential applications in nanotechnology or pharmacology. The first class of compounds consists of Schiff bases and corresponding copper complexes. We investigated structural and electronic properties of these complexes searching for correlations among the information obtained experimentally and by electronic structure calculations. In special, in the study of the competition for the Cu ion between Schiff bases and the albumin protein, we show the influence of different factors such as the geometry of the ligands and their electronic structure. The second class of ligands focused in our studies are modified DNA bases coordinated to copper, where EPR studies have shown ferromagnetic interactions among the metal centers. We studied in this case the influence of the charge state and of the backbone in the magnetization of the Cu chain. In all cases presented here, we used ab-initio electronic structure calculations in the framework of the Density Functional Theory (DFT). This has been done using the CP-PAW code and the Gaussian03 code.