CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Este trabalho foi motivado pelas propriedades diversas e mirÃade de aplicaÃÃes do magnetismo no contexto tecnolÃgico atual, dos quais enfatizamos o papel da magnetizaÃÃo e ondas de spin em sistemas magnÃticos bidimensionais tais com redes quadradas e hexagonais. As ondas de spin tem trazido avanÃos outrora nÃo imaginados e tem favorecido em demasia a construÃÃo de dispositivos mais ecientes nos ramos da eletrÃnica e transporte de informaÃÃes, alÃm de ncar novas perspectivas ainda exploradas conceitualmente. Assim entende-se a importÃncia do tema e procuramos estudar as ondas de spin em um ferromagneto bidimensional exposto a interaÃÃes magnÃticas de diferentes naturezas (troca, anisotrÃpica, Zeeman e dipolar) no intuito de montar a relaÃÃo de dispersÃo dos modelos propostos e construir o espectro da teoria, ou seja, a relaÃÃo energia/vetor de onda. Ademais, plotamos outras relaÃÃes da energia com parÃmetros importantes no foco de melhor entender a evoluÃÃo da energia do sistema, alÃm de que investigamos as inuÃncias da orientaÃÃo da rede frente à magnetizaÃÃo externa. / Este trabalho foi motivado pelas propriedades diversas e mirÃade de aplicaÃÃes do magnetismo no contexto tecnolÃgico atual, dos quais enfatizamos o papel da magnetizaÃÃo e ondas de spin em sistemas magnÃticos bidimensionais tais com redes quadradas e hexagonais. As ondas de spin tem trazido avanÃos outrora nÃo imaginados e tem favorecido em demasia a construÃÃo de dispositivos mais ecientes nos ramos da eletrÃnica e transporte de informaÃÃes, alÃm de ncar novas perspectivas ainda exploradas conceitualmente. Assim entende-se a importÃncia do tema e procuramos estudar as ondas de spin em um ferromagneto bidimensional exposto a interaÃÃes magnÃticas de diferentes naturezas (troca, anisotrÃpica, Zeeman e dipolar) no intuito de montar a relaÃÃo de dispersÃo dos modelos propostos e construir o espectro da teoria, ou seja, a relaÃÃo energia/vetor de onda. Ademais, plotamos outras relaÃÃes da energia com parÃmetros importantes no foco de melhor entender a evoluÃÃo da energia do sistema, alÃm de que investigamos as inuÃncias da orientaÃÃo da rede frente à magnetizaÃÃo externa.

[pt] Diante da importância terapêutica dos 1,2,3-triazóis e da versatilidade da reação de cicloadição 1,3-dipolar de Huisgen catalisada por cobre (reação CuAAC), o presente trabalho propõe a síntese de novos 1,2,3-triazóis-1,4-dissubstituídos abordando-se o conceito de hibridização molecular que associa ao núcleo triazólico outros grupos farmacofóricos privilegiados. Os compostos sintetizados foram divididos em duas séries e avaliados quanto ao potencial anticâncer, antileishmanial e distúrbios do sistema do nervoso central. Para obtenção da primeira série de triazóis utilizou-se como precursores aril azidas preparadas a partir de anilinas e éter propargílicos obtidos a partir de fenóis. A etapa chave da reação de CuAAC levou a obtenção dos 1,2,3-triazóis-1,4-dissubstituídos com rendimentos entre 50 e 85 porcento. Os compostos obtidos foram avaliados em diferentes linhagens celulares de glioblastoma (GBM, U87), incluindo linhagens celulares humanas altamente resistentes como a GBM02, GBM95, onde os compostos 2,2- (4,4-((1,3-phenilenebis(oxi))bis(methileno))bis(1H-1,2,3-triazol-4,1diyl))dibenzaldeído e (E)-4-metil-N-(2-(4-(fenoximetil)-1H-1,2,3triazolil)benzilideno)benzenosulfonohidrazida foram os mais ativos, com IC50 de 28,7 e 30,3 uM, respectivamente. Também foram avaliados nas linhagens de câncer de pulmão e próstata (A549, 22Rv1), entretanto, os compostos analisados não apresentaram atividade frente a estas linhagens celulares. Para a síntese da segunda série de compostos híbridos, tais quais os a-hidroxi-1,2,3-triazóis e benzocromenostriazóis, utilizou-se como materiais de partida aril azidas, preparadas através de ácidos aril borônicos e álcoois propargílicos, preparados a partir de benzaldeídos comerciais. A reação CuAAC na presença de metóxido de sódio levou a obtenção dos novos a-hidroxi-1,2,3-triazóis com rendimentos entre 35 e 75 porcento. A partir dos a-hidroxi-1,2,3-triazóis obtidos, realizou-se a reação de ativação C-H catalisada por paládio para obtenção benzocromenos-triazóis com rendimentos entre 35 e 40 porcento. Esses compostos foram avaliados como inibidores do transportador de glicina (Gly T1), transportadores relacionados a distúrbios neurológicos, e o composto (2-bromofenil)(1-(4-bromofenil)-1H-1,2,3-triazol-4-il)metanol apresentou 42porcento de inibição e IC50 de 13 uM, sendo este o melhor resultado de toda a série. Os compostos obtidos foram avaliados quanto a atividade antileishmanial (L. amazonenses), sendo que os compostos 2,2-(4,4-((1,3- phenilenebis(oxi))bis(methileno))bis(1H-1,2,3-triazol-4,1diyl)) dibenzaldeído e (E)-4-metil-N-(2-(4-(fenoximetil)-1H-1,2,3triazolil)benzilideno) benzenosulfonohidrazida apresentaram os melhores resultados, com IC50 de 8,85 e 8,81 uM, respectivamente. Todos os compostos sintetizados foram caracterizados por técnicas de espectroscopia de ressonância magnética nuclear (RMN), infravermelho (IV) e espectrometria de massas (CG-MS). / [en] In view of the therapeutic importance of 1,2,3-triazoles and the versatility of the copper-catalyzed Huisgen 1,3-dipolar cycloaddition (CuAAC), the present work proposes the synthesis of new compounds containing 1,2,3-triazoles-1,4-disubstituted derivatives by addressing the concept of molecular hybridization to obtain various triazole-containing compounds associated with other privileged pharmacophoric groups. The compounds synthesized were divided into two series and evaluated for their anticancer potential, as antileishmanial and central nervous system disorders. In order to the first series of triazoles, aryl azides were prepared from commercial anilines and propargylic ethers were obtained from commercial phenols. The key step of the CuAAC reaction afforded of 1,2,3-triazoles-1,4-disubstituted 50 - 85 percent in yields. All compounds were evaluated in different glioblastoma cell lines (GBM), including highly resistant human cell lines such as GBM02, GBM95, in which compounds 2,2-(4,4-((1,3 henylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))dibenzaldehyde and (E)-4-methyl-N-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)benzylidene)benzenesulfonohydrazide were the most active, with IC50 of 28.7 and 30.3 uM, respectively. The triazole derivatives were also evaluated for the lung and prostate cancer strains (A549, 22Rv1), however, the compounds analyzed did not show activity in these cell lines. For the synthesis of the second series of hybrid compounds such as a-hydroxy-1,2,3-triazoles and benzochromenes-triazoles, aryl azides were prepared from aryl boronic acids and the propargylic alcohols from commercial benzaldehydes. The CuAAC reaction in the presence of sodium methoxide provided the novel a-hydroxy-1,2,3-triazoles in 35 and 75 percents yields. The a-hydroxy-1,2,3-triazoles, were aplied palladium-catalyzed intermolecular (C-O) cyclization reaction and provided benzocromenes-triazoles in 35-40 percent yields. These compounds were evaluated as inhibitors of glycine transporter (Gly T1), which are related to neurological disorders. Therefore, compound (2-bromophenyl) (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methanol showed the best result with 42 percent of inhibition and IC50 of 13 uM. All compounds were avaluated for antileishmanial activity (L. amazonenses), compounds 2,2-(4,4-((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))dibenzaldehyde and (E)-4-methyl-N-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)benzylidene)benzenesulfonohydrazide presented the best results, with IC50 de 8,85 e 8,81 uM, respectively. All the compounds synthesized were characterized by nuclear magnetic resonance (NMR), infrared (FTIR) spectroscopy and mass spectrometry (GC-MS) techniques.

Estudamos o comportamento crítico do modelo de Ising com interação dipolar, em redes bidimensionais regulares. Este modelo apresenta um cenário fenomenologicamente rico devido ao efeito de frustração causado pela competição entre as interações de troca do Ising puro e a interação dipolar. A criticalidade do modelo foi estudada a partir das relações de escala de tamanho finito para os zeros da função de partição no plano complexo da temperatura. Esta abordagem nunca foi utilizada no estudo do modelo em questão. Nosso estudo se baseia em simulações de Monte Carlo usando o algoritmo multicanônico. O objetivo deste trabalho é obter a temperatura crítica em função do acoplamento (razão entre as intensidades dos acoplamentos ferromagnético e dipolar) e construir uma parte do diagrama de fase do modelo. Diferentes partes do diagrama de fase ainda não apresentam indicações conclusivas a respeito da ordem das linhas de transição. Em particular, há evidências na literatura de um ponto tricrítico para no intervalo [0.90,1.00], mas sua localização precisa não é conhecida. Nossas simulações indicam que o ponto tricrítico não se localiza no intervalo acima. Nossos resultados mostraram que, para [0.89,1.10], a fase do tipo faixas com h=1 passa para a fase tetragonal através de uma transição de segunda ordem. A análise de FSS para os zeros da função de partição na variável temperatura, apresenta, para =1.20, uma transição de fase de segunda ordem e para =1.30, uma transição de fase de primeira ordem. Dessa forma, o ponto tricrítico ocorre somente entre =1.20 e 1.30. Realizamos um estudo complementar baseado na abordagem microcanônica e observamos duas transições de fase de segunda ordem para =1.20 e duas transições de fase de primeira ordem para =1.30, que indica a presença da fase nemática intermediária. / We study the critical behavior of the dipolar Ising model on two-dimensional regular lattices. This model presents a phenomenologically rich scenario due to the effect of frustration caused by the competition between the pure Ising interaction and the dipolar one. To study the criticality of this model we apply finite size scaling relations for the partition function zeros in the complex temperature plane. The partition function zeros analysis has never been used before to study such model with long-range interactions. Our study relies on Monte Carlo simulations using the multicanonical algorithm. Our goal is to obtain the critical temperature as a function of the coupling (the ratio between the ferromagnetic and dipolar couplings) to construct a part of the phase diagram. Different parts of the phase diagram do not present a conclusive results about the order of the phase transition lines.In particular, there is evidence of a tricritical point for [0.90,1.00], but its precise location is unknown. Our simulations indicate that the tricritical point is not located in the above range. Our FSS analysis show that for =1.20 the striped-tetragonal transition is a second-order phase transition and for =1.30 it is a first-order one. Thus, the tricritical point must occur between =1.2 and =1.3. We have used a microcanonical approach to study the criticality of this model too. This approach indicates two second-order phase transitions for =1.20 and two first-order phase transitions for =1.30. Therefore, it presents evidences for the presence of an intermediate nematic phase.

Sistemas complexos que apresentam interações competitivas são ubíquos na natureza. Obter descrições adequadas das propriedades termodinâmicas desses sistemas é um desafio para o entendimento de uma série de processos químicos e físicos. Soluções analíticas em termos da Mecânica Estatística são extremamente difíceis de serem obtidas para esses sistemas. Isso faz com que o uso de simulações numéricas seja, na maioria dos casos, a única abordagem possível. Nesta Tese avaliamos o desempenho de duas classes de algoritmos de Monte Carlo generalizados empregados na determinação da natureza das transições de fase em dois sistemas complexos: o modelo de Ising dipolar bidimensional (2D) e um modelo mínimo para descrever proteínas. Na primeira classe, a qual representa os algoritmos seriais, incluimos os algoritmos multicanônico (MUCA) e de amostragem entrópica (ES), também conhecidos como algoritmos de amostragem uniforme. Na segunda classe, que diz respeito aos algoritmos paralelizáveis, incluimos o algoritmo canônico de Metropolis associado ao método de troca entre réplicas (REM). Para ambas as classes introduzimos contribuições metodológicas visando o aumento da eficiência na obtenção das propriedades canônicas e microcanônicas dos modelos. No caso dos algoritmos de amostragem uniforme, caracterizamos protocolos baseados na contagem de viagens de ida e volta que otimizam a determinação dos pesos de amostragem, e dessa maneira, aumentam a eficiência na obtenção da densidades de estados. Com relação ao uso de simulações canônicas implementadas com o REM, introduzimos o método ST-WHAM-MUCA como uma nova maneira de calcular a entropia microcanônica, associando o inverso da temperatura estatística obtida via ST-WHAM às equações de recorrência do algoritmo MUCA. A partir de simulações canônicas para os dois modelos estudados, mostramos que a termoestatística microcanônica obtida via ST-WHAM é equivalente àquela obtida pelo algoritmo MUCA, mesmo para a região onde ocorrem transições de fase de primeira ordem e uma não concavidade é observada na entropia microcanônica. Além dos estudos sobre a metodologia empregada na implementação dos algoritmos, realizamos contribuições para o entendimento da criticalidade nos modelos. Em particular, determinamos os aspectos críticos no modelo de Ising dipolar 2D para dois cenários distintos. Para o Cenário I, onde apenas uma transição entre as fases de faixas e tetragonal é observada, empregamos o algoritmo MUCA aliado à metodologia de obtenção dos zeros complexos da função de partição canônica. Nesse caso, foi possível determinar a natureza contínua da transição de fase faixas tetragonal, excluindo um possível ponto trícritico, como sugerido na literatura para a região h=1 do diagrama de fases. Para o Cenário II, o qual descreve uma região que apresenta duas transições de fase em decorrência do aparecimento de uma fase nemática entre as fases de faixas e tetragonal, mostramos que o algoritmo MUCA apresenta problemas mesmo para redes pequenas. Utilizando o algoritmo de Metropolis associado ao REM, realizamos simulações para uma rede de tamanho L=72. A partir da análise via ST-WHAM dessas simulações, obtivemos estimativas para o inverso da temperatura microcanônica, as quais sugerem que ambas transições de fase, faixas-nemática e nemática-tetragonal, sejam de primeira ordem, excluindo a possibilidade de uma transição de Kosterlitz-Thouless (KT). Também realizamos simulações utilizando o algoritmo de Metropolis associado ao REM para estudar a criticalidade em proteínas descritas por um modelo mínimo. Nesse estudo caracterizamos a termoestatística microcanônica das transições de enovelamento de quatro cadeias polipeptídicas com conhecida propensidade à formação de agregados. Nossos resultados sugerem que a ausência de barreiras na energia livre favorece a presença de conformações parcialmente desenoveladas, o que facilitaria a agregação das proteínas. Por fim, introduzimos o raio de giração hidrofóbico como parâmetro de ordem para a transição de enovelamento. Além de fornecer resultados condizentes com a descrição microcanônica, essa quantidade pode ser utilizada mesmo que não existam informações sobre o estado nativo. / Complex systems which present competitive interactions are ubiquitous in nature. Obtaining adequate descriptions of the thermodynamic properties of these systems is a major challenge to understand many chemical and physical processes. Analytical solutions in terms of Statistiscal Mechanics are extremely hard to obtain for these systems. Thus, in most cases numerical simulations become the only possible approach. In this Thesis we evaluate the performance of two categories of generalized Monte Carlo algorithms employed to determine the nature of phase transitions in two complex systems: the two-dimensional (2D) dipolar Ising model and a minimal model to describe proteins. In the first category, which represents serial algorithms, we include the multicanonical (MUCA) and entropic sampling (ES) algorithms, which are known as flat histogram algorithms. In the second category, which concerns parallelizable algorithms, we include the Metropolis algorithm associated with replica exchange method (REM). For both categories we introduce methodological contributions aiming the increase of efficiency in obtaining the canonical and microcanonical properties of the models. In case of flat histogram algorithms, we characterized protocols based on round trip counting to optimize the determination of the sampling weights, and therefore increasing the efficiency in obtaining the density of states. Regarding the use of canonical simulations implemented with REM, we introduce ST-WHAM-MUCA as a new method to evaluate the microcanonical entropy, associating the inverse of the statistical temperature obtained from ST-WHAM with the recursions equations of MUCA algorithm. From canonical simulations for both models, we show that the microcanonical thermostatistics obtained via ST-WHAM is equivalent to that obtained by MUCA algorithm, even for a region where a first order phase transition takes place and a non concavity is observed in the microcanonical entropy. In addition to the studies about the methodology employed in implementation of the algorithms, we present the contributions we make to understand the criticality in the models. In particular, we determined the critical aspects of the 2D dipolar Ising model for two different scenarios. For Scenario I, where only one transition is between the stripe and tetragonal phases is observed, we use MUCA algorithm associated with the analysis of the complex zeros from the canonical partition function. In this case, it was possible to determine the continuous character of the stripe-tetragonal phase transition, excluding the existente of a tricritical point, as suggested in the literature for the h=1 region in the phase diagram. For Scenario II, which describe a region that presents two phase transitions due to the appearance of a nematic phase between the stripe and tetragonal phases, we show that the MUCA algorithm present problems even for small lattices. Using the canonical Metropolis algorithm with REM, we run simulations for a lattice with size L=72. From ST-WHAM analysis of these simulations, we obtained estimates for the microcanonical inverse temperature, which suggests that both phase transitions, stripe-nematic and nematic tetragonal, are first order, excluding the possibility of a Kosterlitz-Thouless (KT) transition. We also performed simulations using the canonical Metropolis algorithm associated with the REM to study the criticality in proteins described by a minimal model. In this study we characterized the microcanonical thermostatistics of the folding transitions of four polypeptide chains with known propensity to form aggregates. Our results suggest that the absence of a free-energy barrier favors the presence of partial unfolded conformations, which could facilitate the aggregation of the proteins. Finally, we introduce the hydrophobic radius of gyration as an order parameter for the folding transition. In addition to provide consistent results with the microcanonical description, this quantity can be used even if there is no information about the native state.

Neste trabalho exploramos o uso de sequências de pulsos de Ressonância Magnética Nuclear de Estado Sólido (RMN-ES) que utilizam o acoplamento dipolar magnético heteronuclear para o estudo de reorientações de segmentos moleculares no regime intermediário, testando-as em amostras modelo a fim de verificar suas eficiências. Paralelamente, simulações numéricas foram realizadas juntamente com cálculos analíticos para a melhor compreensão dos efeitos experimentais observados nessas sequências de pulsos. A primeira proposição, baseia-se no uso de Perfis de Hartmann-Hahn obtidos utilizando a Transferência de Polarização Cruzada (CPMAS) sob desacoplamento dipolar homonuclear Lee-Goldburg (LG), usando a interação dipolar heteronuclear como sonda do movimento molecular. A segunda proposição consiste em uma variação das técnicas DIPSHIFT e Time Constant recDIPSHIFT , o T2-recDIPSHIFT, segundo a qual, em condições favoráveis, é possível quantificar parâmetros dinâmicos relacionados aos movimentos moleculares no regime intermediário de sistemas fracamente acoplados pela interação dipolar magnética heteronuclear ou com geometrias de movimento de baixa amplitude. Por fim, propomos um novo método analítico para quantificação de parâmetros dinâmicos em experimentos de Separação de campo locais (SLF), baseado no método de Anderson-Weiss. Demonstramos a precisão do método analítico comparando curvas de Time Constant recDIPSHIFT para diversas taxas e geometrias de movimento obtidas pela aproximação analítica e pelo cálculo exato, além de efetuar um teste experimental em uma amostra modelo. / In the present work we explore the use of Solid State Nuclear Magnetic Resonance (NMR) pulse sequences which use the heteronuclear dipolar magnetic coupling to study local rotations of molecular groups in the intermediate-regime of motion, testing them in standard samples in order to verify their efficiency. Simultaneously, numerical simulations and analytical calculations were performed to understand the experimental artifacts observed in these new pulse sequences. The first proposal, based on using Hartmann-Hahn matching profiles obtained by using the Cross Polarization transfer (CPMAS) under Lee-Goldburg homonuclear decoupling (LG), utilizing the heteronuclear dipolar interaction as probe of the molecular motion. The second proposal consists in a variation of DIPSHIFT and Time Constant recDIPSHIFT pulse sequences, dubbed T2 - recDIPSHIFT, whereby, in favorable conditions, it is possible to quantify molecular dynamic parameters of systems weakly coupled by heteronuclear dipolar interaction or to probe small-amplitude molecular motions. Finally, we proposed a new analytical method to describe Separated Local Field experiments (SLF), based upon the Anderson-Weiss approximation. We demonstrate the accuracy of the method comparing the Time Constant recDIPSHIFT curves for several rates and geometries of motion obtained by the analytical approximation and exact calculation, besides an experimental test has been performed in a model sample.

The thesis aims at methodological developments in Nuclear Magnetic Resonance (NMR) and study of oriented samples like liquid crystals and single crystals and powder samples. Though methodological development in solid state NMR (ss-NMR) has gone far ahead, this work attempts to contribute some novel methods in this direction. The work presented here falls into two categories (i) methodological developments for obtaining information on anisotropic interactions and (ii) experiments which utilize the existing methodologies to study systems of interest under static condition and also under sample spinning at the Magic Angle. In the solid state, dipolar couplings play a crucial role. On the one hand these couplings could be used to transfer polarization from an abundant nucleus to a rare nucleus and increase the sensitivity of the rare nucleus. On the other hand, the measurement of dipolar couplings itself is crucial for extracting structural and dynamic information. A third aspect is that dipolar couplings could be used to obtain correlation, say between two different nuclear species or between the same kind of nuclei as in an exchange experiment. A major part of this thesis deals with all three aspects mentioned above. The thesis presents a new heteronuclear polarization transfer scheme which is devoid of some of the short comings of the existing and well-known polarization transfer schemes. This pulse sequence has been found to be useful in different contexts involving both spin ½ and spin 1 nucleus. The use of dipolar couplings for obtaining correlation in both static oriented systems and in powder samples has been illustrated. In the case of the powder sample, the study has been useful in obtaining useful orientation information. Finally, chemical shifts are known to be indicators of finer structural features of molecules in solution and solid state. 13 C MAS NMR studies have been exploited in understanding these structural features of short peptides containing prolines in the solid state and for comparing with their structures in solution. Chapter 1 covers the theoretical aspects required for the experimental work described in the thesis. A brief description of NMR has been followed by the explicit description of various interaction Hamiltonian’s in ss-NMR. Subsequently the experimental and the theoretical tools needed for ss-NMR study like Magic Angle Spinning (MAS), Cross-Polarization, Homo/Heteronuclear decoupling schemes have also been discussed. Chapter 2, describes a new heteronuclear polarization transfer scheme for oriented samples – named DAPT (Dipolar Assisted Polarization Transfer) and its application to different systems. DAPT uses a homonuclear decoupling sequence such as BLEW-12 for effecting heteronuclear polarization transfer. The chapter has been divided into five related parts. Section 2(A) starts with an introduction to the existing heteronuclear polarization transfer schemes. Subsequently the theoretical background of the new sequence is presented. Experimental implementation of the sequence in an oriented system, liquid crystal is presented and is compared with the well-known polarization transfer scheme, Hartmann-Hahn Cross Polarization (HH-CP). In 2(B) the implementation of the sequence as a local field spectroscopy for measuring heteronuclear dipolar couplings is presented. After initial discussion about local field spectroscopy and its relevance in ss-NMR, the improvements made in the earlier mentioned sequence along with its 2D implementation in a liquid crystal sample are described. A comparative study is also presented using DAPT with various other homonuclear decoupling sequences. Chapter 2(C) deals with the extension of DAPT to spin-1 systems. The difficulties in setting up the HH-CP in spin-1 systems are highlighted. Experimental demonstrations on a test sample of oriented CD3 I and also on a deuterated liquid crystal is described. The sequence has been incorporated as part of a 2D correlation experiment, where the F1 dimension provides the quadrupolar couplings of deuterium and the F2 the chemical shifts of the attached carbons. The comparison of the sequence with HH-CP, its merits and demerits are discussed and the potential applications are highlighted. Chapter 2(D) deals with the relatively less studied transition in 14N nucleus, known as the Overtone-Transition (OT). An introduction to OT and its relevance is provided in the beginning followed by the extension of DAPT in exciting and detecting OT. The experiments have been done on a single crystal of a model peptide, N-Acetyl-DL-Valine and are compared with the conventional method. Amide proton chemical shifts are also measured using DAPT in an indirect way. The advantages and the future application in studying OT are also discussed. Chapter 2(E) discusses the extension of DAPT to the single crystal of NAV and in identifying the molecules in the unit cell. The SLF spectrum of NAV is complicated due to the presence of two magnetically in-equivalent molecules in the unit cell and with pairs of splitting for each C - 1H and C - 1H pairs. The dipolar couplings are extracted from the experiment and with the aid of a MATLAB program and by incorporating the crystal coordinates, identification of C-1H and C-1H pairs belonging to a particular molecule have been carried out. Chapter 3 describes a novel and useful modification of the well-known Separated Local Field (SLF) sequence in solid state known as PISEMA (Polarization Spin Exchange at the Magic Angle). PISEMA is a popular technique for measuring heteronuclear dipolar couplings in oriented in oriented biological membranes and in liquid crystals. While it has several advantages such as a large dipolar scaling factor, narrow line-widths in the dipolar dimension and ease of setting up etc it suffers from a major problem. The technique is highly sensitive to the proton off-sets which affect the measured dipolar couplings. In the present chapter the origin of this problem has been analyzed in detail and a solution has been proposed. The modification to the experiment has been implemented on a liquid crystal and the off-set independence of the new sequence has been demonstrated. Further studies on a more rigid system such as a solid single crystal has been used to verify the effect of the modification on homonuclear decoupling efficiency and the consequent effects on the line widths in addition to off-set independence. The advantages of the proposed method over the existing one in terms of line-width and robustness in measuring heteronuclear dipolar couplings are demonstrated. Chapter 4 presents a study of deuterium exchange on a di-peptide. Deuterium as well as carbon-13 NMR spectroscopy has been extensively used earlier on static powder samples for studying exchange phenomena. In the present study we have applied the methodology for obtaining relative N-D vector orientation in a di-peptide. The magnetization exchange between deuterium nuclei through the dipolar couplings between them has been monitored. The need to match the quadrupolar split energy levels of two different deuterium’s differently oriented in the magnetic field requires that the sample be spun slowly. Characteristic exchange powder patterns were obtained which were used to infer relative orientation information. Comparison with the crystal structure indicates that the magnetization is likely to be inter-molecular rather than intra-molecular. The chapter follows the following sequence. A brief description about the importance of exchange studies in ss-NMR is presented. A theoretical approach is followed by a discussion of the angular dependence of the frequencies and the visualization of the mutual re-orientation angles. The motivation of the project followed by the experimental techniques, especially the use of slow MAS ~ 100 Hz in exchange studies are also presented. Initial studies have been carried out on di-methyl sulphone to check the reproducibility of the earlier reported results and later the sequence is extended to amide proton deuterated di-glycine. The 2D exchange spectrum recorded under slow MAS is then discussed in the context of the crystal structure and possible amide deuteriums involved in the exchange process are inferred. Chapter 5 discusses the natural abundant 13C and 15N NMR spectroscopy in the solid state in designed tri-peptides containing prolines. Proline is a unique amino acid because of it torsion angle values and is responsible for the turns and the globularity of the proteins. The well studied SH3 domain protein often binds to short peptides containing prolines and hence these study gains importance. Three peptides containing prolines were taken up for study. For peptide (1), the conformation was observed as cis/trans in the solution state and for the other two peptides it was all trans. The X-ray studies showed that peptide (1) has two molecules in the unit cell with both cis conformation. This motivated us to look at the solid state spectra of the peptides. Chemical shifts are signatures of conformers and it was established from the chemical shift differences that there exist two molecules in the unit cell for peptide (1), both in cis conformation. The conformers for the other two peptides predicted by NMR chemical shifts also matched with those obtained from X-ray studies. This opens up the possibility of using simple NMR measurements in the solid state as tools for secondary structure determination in larger peptides and proteins.

In der Kernspinresonanzspektroskopie (NMR) treten drei Effekte auf, die paramagnetische und diamagnetische Moleküle in isotroper Lösung unterscheiden: residuale dipolare Kopplung (RDC), Pseudokontaktverschiebung (PCS) und paramagnetische Relaxationsverstärkung (PRE). Alle drei Effekte sind abhängig von intermolekularen Winkeln und Abständen und können daher Informationen über die Struktur und Dynamik des Moleküls liefern. Um diese Informationen zu erhalten, muss das Molekül paramagnetische Eigenschaften aufweisen. Eine der heutzutage gebräuchlichen Methoden verwendet kleine molekulare Tags, die paramagnetische Metallionen koordinieren. Die meisten dieser Tags binden über eine Disulfidbrücke an Cysteine an der Proteinoberfläche. Um diese Methode für DNA anzuwenden werden daher neue Taggingstrategien benötigt. Im Rahmen dieser Arbeit wurde eine modifizierte Nukleobase synthetisiert, mit der ein Schwefelatom in die DNA eingebracht werden kann. Diese Methode erlaubt es, jeden Tag an die DNA zu binden, der als Verbindungsmethode eine Disulfidbrücke nutzt. Mit der Nukleobase wird eine Kohlenstoff-Dreifachbindung in die DNA eingefügt und mit Hilfe einer dipolaren Cycloaddition wird die freie Thiolgruppe eingebracht. Die modifizierte Nukleobase wurde erfolgreich an einem selbstkomplementären DNA-Strang (24 Nukleobasen) getestet. Die Nukleobase wurde während der Synthese der DNA eingefügt und der mit Lutetium, Terbium oder Thulium vorbeladene Cys-Ph-TAHA Tag wurde über eine Disulfidbrücke an die DNA gebunden. Die Beladung des Tags und die Taggingreaktion verliefen hierbei quantitativ. Nach diesem Erfolg war es ein Hauptaspekt dieser Arbeit, eine verlässliche und reproduzierbare Aufreinigungs- und Probenvorbereitungsmethode zu entwickeln. Diesem Punkt kommt besondere Bedeutung zu, da das Phosphatrückgrat der DNA, im Gegensatz zu Proteinen, Metallionen koordinieren kann. Im Theorieteil dieser Arbeit ist eine komplette Herleitung der drei Hauptmerkmale paramagnetischer NMR gegeben. Diese Herleitung beginnt bei Grundbegriffen des Magnetismus und neben den Gleichungen für RDCs, PCSs und PREs werden Ausdrücke für den dipolaren Hamiltonoperator, Kreuzrelaxationsraten, kreuzkorrelierte Relaxationsraten, durch Alignment induzierte RDCs, Korrelationsfunktionen und spektrale Dichten gegeben. Das zweite Thema dieser Arbeit basiert auf einem weiteren paramagnetischen Effekt. Um der reduzierten Empfindlichkeit der Kernspinresonanzspektroskopie verglichen mit anderen Spektroskopiemethoden entgegenzuwirken, wurden viele Methoden entwickelt, die auf eine Erhöhung der Polarisierung der Atomkerne zielen, d.h. um sogenannte hyperpolarisierte Kerne zu erzeugen. Eine dieser Methoden, die photochemisch erzeugte dynamische Kernpolarisierung (photo CIDNP), basiert auf kurzlebigen Radikalen, die durch direkte Laserbestrahlung der Probe im Magneten erzeugt werden. Im Rahmen dieser Arbeit wurde ein photo CIDNP Aufbau entworfen, gebaut und getestet. Die ersten Experimente und Resultate mit Triethylendiamin, L-Tyrosin und 3-Fluor-L-tyrosin zeigen die Vorteile und Grenzen dieser Methode auf. Für 3-Fluor-L-tyrosin wurde eine komplette Analyse des Relaxationsverhaltens, einschließlich der Kreuzrelaxation und der kreuzkorrelierten Relaxation, durchgeführt.

Organic-inorganic nanostructured composites are nowadays integrated in the field of material science and technology. They are used as advanced materials directly or as precursors to novel composites with potential applications in optics, mechanics, energy, catalysis and medicine. Many properties of these complex materials depend on conformational rearrangements in their inherently dynamic organic parts. The focus of this thesis is on the study of the molecular mobility in ordered nanostructured composites and lyotropic mesophases and also on the development of relevant solid-state NMR methodologies. In this work, a number of new experimental approaches were proposed for dipolar NMR spectroscopy for characterizing molecular dynamics with atomic-level resolution in complex solids and liquids. A new acquisition scheme for two-dimensional dipolar spectroscopy has been developed in order to expand the spectral window in the indirect dimension while using limited radio-frequency power. Selective decoupling of spin-1 nuclei for sign-sensitive determination of the heteronuclear dipolar coupling has been described. A new dipolar recoupling technique for rotating samples has been developed to achieve high dipolar resolution in a wide range of dipolar coupling strength. The experimental techniques developed herein are capable of delivering detailed model-independent information on molecular motional parameters that can be directly compared in different composites and their bulk analogs. Solid-state NMR has been applied to study the local molecular dynamics of surfactant molecules in nanostructured organic-inorganic composites of different morphologies. On the basis of the experimental profiles of local order parameters, physical motional models for the confined surfactant molecules were put forward. In layered materials, a number of motional modes of surfactant molecules were observed depending on sample composition. These modes ranged from essentially immobilized rigid states to highly flexible and anisotropically tumbling states. In ordered hexagonal silica, highly dynamic conformationally disordered chains with restricted motion of the segments close to the head group have been found. The results presented in this thesis provide a step towards the comprehensive characterization of the molecular states and understanding the great variability of the molecular assemblies in advanced nanostructured organic−inorganic composite materials. / <p>QC 20150225</p>

Conselho Nacional de Desenvolvimento Científico e Tecnológico / This work reports the synthesis of a series of 29 new 1-(3-aryl-4,5-dihydroisoxazol-5-yl)methyl-4-trihalomethylpyrimidin-2(1H)-ones which have high pharmacological interest, since they are similar to natural and synthetic nucleosides. These compounds were obtained from 1,3-dippolar cycloaddition reaction between the 1-allyl-(6-aryl)-4-trihalomethylpyrimidin-2(1H)-ones and different benzonitrile oxides, obtained from the selected oximes of general formula ArCH=NOH (where Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, styryl, 2-OHC6H4 e 4-OHC6H4). The reaction conditions employed were highly regioselective, because it was observed the formation of only 3,5-substituted isomer by both NMR spectral analysis and X-ray diffractometry. The compounds were obtained in good yields (58 99%) and were purified from recrystallization or by column chromatography on silica gel. Some the obtained compounds showed antineoplastic activity in vitro against different tumor cell lines. Additionally, three new N3-substituted pyrimidinic dideoxynucleoside analogues were prepared, which were obtained in good yields (88 97%) from the reaction of N-allyl-2-methylthiopyrimidin-4(3H)-one and some of the benzonitrile oxides mentioned above. The reactions for the formation of N3-substituted nucleoside still require optimization. This thesis also described the regiochemisty controled synthesis of two series of pyrazoles, named 5(3)-aryl-3(5)-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides, structural analogues of Celecoxib (14 examples), where aryl = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, furan-2-yl, from the cyclocondensation reaction between 4-aryl-1,1,1-trifluoromethyl-4-methoxy-3-buten-2-ones and 4-hydrazinobenzenosulfonamide hydrochloride. The isolation of either isomer depended on the initial pH medium, where the alkaline pH favored the isolation of the 1,5-substituted isomer at yields of 73 99% and the reaction conducted in acid pH favored the isolation of the 1,3-substituted isomer, with yields of 77 94%. This study also allowed the isolation and spectroscopic characterization of a novel series of 3-aryl(heteroaryl)-5-hydroxy-5-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides (7 examples) in yields of 75 97% with interesting anti-inflammatory and antinociceptive activities in vivo. / Esta tese apresenta a síntese de uma série de 29 moléculas inéditas de 1-(3-aril-4,5-diidroisoxazol-5-il)metil-4-trialometilpirimidin-2(1H)-onas que possuem alto interesse farmacológico, visto que são análogos a nucleosídeos naturais e sintéticos. Esses compostos foram obtidos a partir de reação de cicloadição 1,3-dipolar entre as 1-alil-(6-aril)-4-trialometilpirimidin-2(1H)-onas e diferentes óxidos de benzonitrila, obtidos a partir das oximas selecionadas, de fórmula geral ArCH=NOH (onde Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, Estiril, 2-OHC6H4 e 4-OHC6H4). As condições reacionais empregadas mostraram-se altamente regiosseletivas, uma vez que, por análise dos espectros de RMN e por difratometria de raios-X, observou-se a formação apenas do isômero 3,5-substituído. Os compostos foram obtidos em bons rendimentos (58 99%) e puderam ser purificados a partir de recristalização ou através de coluna cromatográfica em sílica gel. Alguns dos compostos obtidos apresentaram atividade antineoplásica in vitro frente a diferentes linhagens de células tumorais. Também estão apresentados 3 novos análogos nucleosídeos pirimidínicos N3-substituídos, obtidos em bons rendimentos (88 97%) a partir da reação da N-alil-2-metiltiopirimidin-4(3H)-ona e de alguns óxidos de benzonitrila acima citados. As reações para a formação dos nucleosídeos N3-substituídos ainda necessitam de otimização. Nesta tese também está descrito o controle regioquímico para a síntese de duas séries de pirazóis, nomeados 5(3)-aril-3(5)-trifluormetil-(1H-pirazol-1-il)benzenosulfonamidas, análogos estruturais do Celecoxib (14 exemplos), onde aril = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, fur-2-il, a partir da reação de ciclocondensação entre 4-aril-1,1,1-trifluormetil-4-metóxi-3-buten-2-onas e o cloridrato de 4-hidrazinilbenzenosulfonamida. O isolamento de um ou outro isômero dependeu do pH inicial do meio, onde o pH básico favoreceu o isolamento do isômero 1,5-substituido com rendimentos de 73 99% e a reação conduzida em pH ácido favoreceu o isolamento do isômero 1,3-substituído, com rendimentos de 77 94%. Este estudo também possibilitou o isolamento e caracterização espectroscópica de uma série inédita de 3-aril(heteroaril)-5-hidróxi-5-trifluormetil-(1H-pirazol-1-il)benzenosulfonamidas (7 exemplos) em rendimentos de 75 97%, com interessante atividade anti-inflamatória e antinociceptiva in vivo.

Made available in DSpace on 2015-05-14T13:21:13Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2559856 bytes, checksum: 50fe82b4059b56d6e01eb8e3cf66ea70 (MD5) Previous issue date: 2012-10-20 / Financiadora de Estudos e Projetos - Finep / Mesoionic compounds are notable heterocyclic for having the most diverse biological properties, physical and chemical properties. Are defined as flat and non-aromatic heterocyclic Betaines stabilized by electron delocalization. Through an in situ cycloaddition/cicloreversion 1,3-dipolar were obtained two mesoionic, MI-1.1 and MI-1.2 through of the interconversion system 1,3-oxazólio-5-olato (Munchnonas) for 1,3-tiazólio-5-tiolato. A nucleophilic substitution reaction with excess methyl iodide, CH3I, promoted the first modification to the mesoionic system were changed of free base to iodates salts, S-methylated forming derivatives mesoionic, MI-2.1 e MI-2.2. These underwent a cyclodehydration reaction in the presence of acetic anhydride yielding two mesoionic system 1,3-diazolium-5-thiolate, MI-3.1 and MI-3.2, which in turn were alkylated again and originated two derived in the form of iodates salts S-methylated, MI-4.1 and MI-4.2. As the mesoionic and its derivatives: MI-2.1, MI-2.2, MI-3.1, MI-3.2, MI-4.1 and MI-4.2 and unpublished literature. Their structures were elucidated by spectroscopic techniques for RMN 1H and 13C and infrared light through a comparative analysis with existing structures. / Os compostos mesoiônicos são heterocíclicos notáveis por apresentar as mais diversas propriedades biológicas, físicas e químicas. São definidos como betaínas heterocíclicas planas e não aromáticas estabilizadas por deslocalização de elétrons. Através de uma reação in situ de cicloadição/cicloreversão 1,3-dipolar obtiveram-se dois mesoiônicos, MI-1.1 e MI-1.2, através da interconversão do sistema 1,3-oxazólio-5-olato (Munchnonas) para 1,3-tiazólio-5-tiolato. Uma reação de substituição nucleofílica com excesso de iodeto de metila, CH3I, promoveu a primeira modificação no sistema mesoiônico sendo transformados de base livre para sais iodatos S-metilados formando os derivados mesoiônicos, MI-2.1 e MI-2.2. Estes sofreram uma reação de ciclodesidratação na presença de anidrido acético obtendo-se dois mesoiônicos do sistema 1,3-diazólio-5-tiolato, MI-3.1 e MI-3.2, que por sua vez foram alquilados novamente e originaram dois derivados em forma de sais iodatos S-metilados, MI-4.1 e MI-4.2. Sendo os mesoiônicos e seus derivados: MI-2.1, MI-2.2, MI-3.1, MI-3.2, MI-4.1 e MI-4.2 inéditos na literatura. Suas estruturas foram elucidadas por meio de técnicas espectroscópicas de RMN 1H e 13C e infravermelho através de uma análise comparativa com estruturas já existentes.