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This thesis focuses on the development of molecules that target proteins in a previously undescribed manner for the treatment of BRCA deficient cancers. ZINC 13403027, a clerodan-based natural product, was shown to target a protein called Rad52. Cancers possessing loss of function mutations in BRCA1 and BRCA2 are dependent on Rad52 for DNA repair and replication while normal, healthy cells possess multiple DNA repair/replication pathways. Thus, inhibitors of Rad52 may serve as selective anti-cancer drugs for BRCA deficient tumors. ZNIC 13403027 was selected for its high activity in disrupting the ssDNA-Rad52 interaction in a gel-shift assay as well as exhibiting the required inactivity at disrupting the ssDNA-Rad51 interaction. Due to its lack of permeability, a synthetic route amenable to modification has been partially developed. It is thought that a prodrug or bioisostere of ZINC 13403027 could cross the membrane so that the cellular activity of this novel tool molecule may be established. Additionally, an allosteric PARP1 inhibitor, 5F02, was explored. Discussed here is the synthetic route to 5F02 and its analogs. Structure activity relationships were develop in an attempt to increase inhibitory activity and drug-like properties. This thesis reports the success to date on these two projects. / Pharmaceutical Sciences

Using a hydrogen donor and a catalyst for upgrading and increasing oil recovery during in situ combustion is a known and proven technique. Based on research conducted on this process, it is clear that widespread practice in industry is the usage of tetralin as a hydrogen donor. The objective of the study is to find a cheaper hydrogen donor with better or the same upgrading performance. Decalin (C10H18) is used in this research as a hydrogen donor. The experiments have been carried out using field oil and water saturations, field porosity and crushed core for porous medium. Four in situ combustion runs were performed with Gulf of Mexico heavy oil, and three of them were successful. The first run was a control run without any additives to create a base for comparison. The next two runs were made with premixed decalin (5 percent by oil weight) and organometallic catalyst (750 ppm). The following conditions were kept constant during all experimental runs: air injection rate at 3.1 L/min and combustion tube outlet pressure at 300 psig. Analysis of the performance of decalin as a hydrogen donor in in-situ combustion included comparison of results with an experiment where tetralin was used. Data from experiments of Palmer (Palmer-Ikuku, 2009) was used for this purpose, where the same oil, catalyst and conditions were used. Results of experiments using decalin showed better quality of produced oil, higher recovery factor, faster combustion front movement and higher temperatures of oxidation. API gravity of oil in a run with decalin is higher by 4 points compared to a base run and increased 5 points compared to original oil. Oil production increased by 7 percent of OOIP in comparison with base run and was 2 percent higher than the experiment with tetralin. The time required for the combustion front to reach bottom flange decreased 1.6 times compared to the base run. The experiments showed that decalin and organometallic catalysts perform successfully in in situ combustion, and decalin is a worthy replacement for tetralin.

Made available in DSpace on 2016-06-02T19:55:36Z (GMT). No. of bitstreams: 1 5188.pdf: 6910424 bytes, checksum: 50b02c26311d2e058a7ac27b5419e05d (MD5) Previous issue date: 2011-06-08 / Environmental laws and stricter quality specifications have driven the development of technologies for improving the cetane number in diesel fuel. In addition to the saturation of (poly)aromatic compounds, responsible for limited gains, ring opening of at least one ring of (poly)cycloalkane, without loss of yield by cracking, is a promising strategy to maximize this property. Numerous studies have demonstrated the significant performance of Pt, Rh and Ir supported on zeolites for naphthenic ring opening in the hydroconversion of model compounds (naphthalene, tetralin and decalin). This study aimed to systematically assess the role of acid and hydrogenating functions for hydroconversion of decalin. It was also evaluated the effect of activation conditions (calcination and reduction), type of zeolite (Faujasite, FAU, or Beta, BEA), the content and type of metal (Pt, Ir or Rh). The influence of Pt-Ir and Pt-Rh bimetallic systems, as well as the inhibition by H2S, were studied in terms of the performance of these catalysts. For the catalytic precursors prepared, better activity and selectivity to ringopening products were obtained from calcination at 573 K and reduction at 713 K. This performance was consistent with a more homogeneous distribution of metallic particles on the support, and thus greater dispersion of the metallic phase. The reaction steps of ring contraction, ring opening and cracking were consecutive for the hydroconversion of decalin. It is noteworthy that the catalytic systems studied, under the operating conditions employed, yielded up to 45 mol% ring opening products and less than 15 mol% cracking products, at decalin conversions as high as 90 %. The Pt/BEA catalyst presented the best performance, thiotolerance (lower production of cracking products) and thioresistence (selectivity recovery after removal of H2S), followed by the Pt-It/BEA and Ir/BEA catalysts. This study allowed to highlight some peculiarities of the hydroconversion of decalin on noble metal/zeolite catalysts. Although decalin is a saturated molecule, his naphthenic character and probably the presence of a tertiary carbon in its structure, facilitates activation of the molecule directly on the strong acid sites of zeolite, even at relatively moderate temperatures. Thus, it is not necessary to form an olefin on a metal site and undergo subsequent protonation, as in a classical bifunctional mechanism, such as in hydroisomerization and hydrocracking of n-paraffins. However, the hydrogenation component of the catalyst influences the selectivity of the reaction, controlling the process of desorption/adsorption of any intermediate olefins formed. Greater hydrogenation activity implies lower availability of adsorbed carbocations that can be converted to cracking products. This proposition is consistent with the results obtained by varying the type and content of metal, support acidity and poisoning of the hydrogenation sites in the catalysts. / Legislações ambientais e especificações de qualidade mais restritivas têm impulsionado o desenvolvimento de tecnologias visando melhoria de cetano em óleo diesel. Adicionalmente à saturação de (poli)aromáticos, responsável por ganhos limitados, à abertura de pelo menos um anel do (poli)cicloalcano, sem perda de rendimento por craqueamento, consiste em estratégia potencial para maximização desta propriedade. Inúmeros trabalhos vêm demonstrando desempenho significante de catalisadores de Pt, Rh e Ir suportados em zeólitas para abertura de anel naftênico na hidroconversão de compostos-modelo (naftaleno, tetralina e decalina). O presente trabalho teve por objetivo avaliar sistematicamente o papel das funções ácidas e hidrogenantes para a hidroconversão de decalina. Foram abordados os efeitos das condições de ativação (calcinação e redução), do tipo de zeólita (Beta, BEA, ou Faujasita, FAU), do teor e do tipo de metal (Pt, Ir ou Rh). Também foi analisado o efeito de sistemas bimetálicos Pt-Ir e Pt-Rh, bem como a influência da inibição por H2S, no desempenho destes catalisadores. Para os precursores catalíticos preparados, melhores atividade e seletividade aos produtos de abertura de ciclo foram obtidas a partir da calcinação a 573 K e redução em 713 K. Este desempenho foi compatível com uma distribuição mais homogênea de partículas metálicas no suporte e, portanto, maior dispersão da fase metálica. As etapas reacionais de contração, abertura de ciclo e craqueamento são consecutivas para a hidroconversão de decalina. Destacam-se para os sistemas catalíticos estudados e condições operacionais empregadas, rendimentos de produtos de abertura de ciclo de até 45 %mol e craqueamento inferior a 15 %mol, obtidos para conversões de decalina tão elevadas quanto 90 %. O catalisador Pt/BEA apresentou melhores desempenho, tiotolerância (menor seletividade a craqueados na presença de H2S) e recuperação da seletividade após remoção do H2S, seguido pelo bimetálico de Pt-Ir/BEA e monometálico de Ir/BEA. O presente estudo permitiu colocar em evidência algumas peculiaridades da hidroconversão da decalina sobre catalisadores metal nobre/zeólita. Apesar de se tratar de uma molécula saturada, seu caráter naftênico e, provavelmente, a presença de um carbono terciário na sua estrutura, facilita a ativação da molécula diretamente sobre os sítios ácidos fortes da zeólita, mesmo em temperatura relativamente moderadas. Dessa forma, não necessita a formação de uma olefina num sítio metálico para posterior protonação, como num mecanismo bifuncional clássico de hidroisomerização e hidrocraqueamento de n-parafinas. A componente de hidrogenação do catalisador influencia, no entanto, a seletividade da reação, controlando o processo de dessorção/adsorção e hidrogenação das olefinas intermediárias formadas. Quanto maior a atividade hidrogenante, menor a disponibilidade de carbocátions adsorvidos que podem ser convertidos a produtos de craqueamento. Esta proposição é consistente com os resultados obtidos ao se variar o tipo e o teor de metal, a acidez do suporte e pelo envenenamento dos sítios de hidrogenação dos catalisadores.

L'ouverture sélective de cycle (OSC) d'hydrocarbures polycycliques vise à augmenter le nombre de cétane des carburants diesel. OSC efficace peut être atteint par l'hydroconversion sur des catalyseurs bifonctionnels métal noble/fonction acide. La décaline et, à plus faible mesure, le perhydroindane, le butylcyclohexane et la tétraline, ont été utilisés comme molécules modèles pour l'étude des l'OSC de sulfures de métaux de transition (TMSs) supportés sur zéolithes ou silice-alumine amorphe dans un réacteur à lit fixe sous haute pression (5 MPa) avec une concentration élevée d'H2S dans la charge réactionnelle (1 %). Les nombreux produits d'hydroconversion ont été identifiés grâce à la chromatographie gazeuse bidimensionnelle, qui nous a permis de mieux comprendre les mécanismes de réaction. Ce travail a consisté à l'étude de la nature et la charge du SMT et la nature du support. Comparé à la zéolithe seule, le catalyseur RuSx/HY (qui sert de référence) est plus stable et dix fois plus actif avec une sélectivité en produits d'ouverture proche des 30% à 240 °C. Les produits les plus abondants restent les produits d'isomérisation, ce qui suggère que l'acidité du support domine le schéma réactionnel. Quant à l'ajout de TMS, leur rôle est d'activer l'hydrogène, de favoriser les réactions d'hydrogénation/déshydrogénation et limiter le cokage des sites acides. NiSx/HY est aussi performant que les catalyseurs à base de Ru, Ir ou Rh et un effet de synergie est observé pour les catalyseurs ternaires Ni-Ru et Ni-Rh. Toutefois, comparé aux métaux nobles comme l'Ir et le Ru étudiés sans H2S, les catalyseurs sulfures sont quasiment non-hydrogénolysants. Enfin, la zéolithe HY présente des performances proches a la H-Beta mais avec moins de craquage / The selective ring opening (SRO) of polycyclic hydrocarbons aims at increasing the cetane numbers of diesel fuels. Efficient SRO can be achieved through hydroconversion over bifunctional noble metal/acid catalysts. Decalin and, to lower extents, perhydroindan, butylcyclohexane and tetralin, have been used as model molecules to investigate the SRO performances of transition metal sulfides (TMSs) supported on zeolites or amorphous silica-alumina in a high-pressure (5 MPa) flow-fixed bed reactor with a high concentration of H2S in the reactant feed (1 %). The numerous hydroconversion products have been identified using comprehensive two-dimensional chromatography for various levels of reactant conversions, which allowed us to gain insight into the reaction mechanisms. The presence, loading and nature of the TMS, and the nature of the support, have been investigated. With respect to the bare HY zeolite, RuSx/HY (which served as our reference) is more stable and ten times more active, with a ring-opening selectivity of up to 30 % at 240 °C. The most abundant products are skeletal-isomerization ones, which suggests that the acidic support dominates the reaction scheme. The TMS role is to activate hydrogen, catalyze hydrogenation/ dehydrogenation and prevent the coking of acidic sites. NiSx/HY performs similarly to Ru, Ir and Rh-based catalysts, and a synergetic promoting effect is observed for Ni-Ru and Ni-Rh combinations. However, with respect to noble metals such as Ir and Ru under H2S-free conditions, the sulfide counterparts appear much less (if not) hydrogenolytic. As compared to HY, the H-Beta support shows similar performance but promotes cracking