Ischemic injury occurs when the flow of blood is reduced or blocked to an area of the body and can cause significant tissue damage by generation of reactive oxygen species (ROS), activation of apoptotic pathways and through induction of the inflammatory response. Restoration of blood flow and reperfusion of the blocked site, while essential, can generate a second injury that itself needs to be controlled. Together the two injuries are termed ischemia/reperfusion (I/R) injury. This type of injury is frequently encountered in medicine and is a major medical problem. Therapeutic strategies to combat I/R injury include the introduction of compounds that can scavenge ROS or can induce metabolic pathways with the effect of inhibiting apoptosis. Caffeic Acid Phenethyl Ester (CAPE), a polyphenolic compound found in propolis, has been shown to protect a variety of cells types against ROS in vitro and has also been shown to induce a variety of genes including hemeoxygenase 1 (HMOX-1) , an enzyme that has been implicated in a cytoprotective pathway. Despite showing significant cytoprotection of cells against oxidant stress in vitro, CAPE is readily hydrolyzed in plasma and is also quickly removed from circulation. This result may explain the limited cytoprotective effects of CAPE in vivo. We have synthesized a series of CAPE amide derivatives, including Caffeic Acid Phenethyl Amide (CAPA), with the aim of improving CAPE’s stability properties while maintaining the cytoprotective effects of the parent compound. We found that CAPA, in addition to 2 other amide derivatives, were able to protect human umbilical vein endothelial cells (HUVEC) against ROS to a similar degree as CAPE. In addition, we have observed significant improvement in plasma stability of CAPA over CAPE at multiple temperatures. The elimination half-life of CAPA from the systemic circulation was also seen to be significantly improved over CAPE following intravenous administration to male Sprague-Dawley rats. The longer residence time of CAPA over CAPE in circulation may potentially result in greater cytoprotection in vivo. / text

In the context of pharmaceutical development, it is abundantly clear that there is a need for greater understanding and control of crystalline phases. The field of crystal engineering is poised to address such issues and has matured into a paradigm for the supramolecular synthesis of new compounds with desired properties. Crystal structures are unpredictable by nature, however, the interactions that lead to crystal formation are becoming much more predictable. By means of model compound studies, the delineation of the hierarchy of hydrogen bonding between complementary functional groups or supramolecular heterosynthons can be accomplished. Competitive co-crystallization studies along with data extracted from the Cambridge Structural Database (CSD) can be utilized in understanding the reliability of supramolecular heterosynthons without the need for endless co-crystallization experiments. In effect, this ability to understand supramolecular heterosynthons can allow crystal engineers to rationally design co-crystals with a high rate of success. It has been suggested that pharmaceutical co-crystals could play a significant part in the future of API formulation since in principle they will outnumber pharmaceutical salts, polymorphs and solvates combined. The focus of this thesis is the understanding of the primary amide functional group and its hydrogen bonding capabilities; as well as the synthesis of model compounds in order to develop a blueprint for the design of pharmaceutical co-crystals using APIs that contain a primary amide functional group.

Rationale: In the breast cancer setting, anti-cancer therapies, including Doxorubicin (DOX) and Trastuzumab (TRZ), are associated with an increased risk of cardiotoxicity. There is a need to develop prophylactic cardioprotective agents to mitigate the cardiotoxic side effects of these common anti-cancer drugs. Objective: To investigate whether the anti-oxidant, N-acetylcysteine amide (NACA), can attenuate the drug-induced heart failure caused by DOX+TRZ in a murine model. Methods: A total of 100 female mice received one of the following drug regimens: i) saline; ii) NACA; iii) DOX; iv) TRZ; v) DOX+TRZ; vi) NACA+DOX; vii) NACA+TRZ; and viii) NACA+DOX+TRZ. Serial echocardiography was performed over a 10-day study period, after which the mice were euthanized for histological and biochemical analyses. Results: In mice receiving DOX, left ventricular ejection fraction (LVEF) decreased from 73±4% to 43±2% at day 10. In mice receiving DOX+TRZ, LVEF decreased from 72±3% to 32±2% at day 10. Prophylactic administration of NACA to mice receiving DOX or DOX+TRZ was cardio-protective with an LVEF of 62±3% and 55±3% at day 10, respectively. Histological and biochemical analyses demonstrated loss of cellular integrity, increased oxidative stress (OS), and increased cardiac apoptosis in mice treated with DOX+TRZ which was attenuated by the prophylactic administration of NACA. Conclusion: NACA attenuates the cardiotoxic side effects of DOX+TRZ in a murine model of chemotherapy induced cardiac dysfunction by decreasing OS and apoptosis. / October 2015

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Protein dynamics play a key role in enzyme-catalyzed reactions. Vibrational spectroscopy provides a method to follow these structural changes and thereby describe the reaction coordinate as a function of space and time. A vibrational spectroscopic technique, reaction-induced FTIR spectroscopy, has been applied to the study of the oxygen-evolving complex (OEC) of photosystem II (PSII). In plant photosynthesis, PSII evolves oxygen from the substrate, water, by the accumulation of photo-oxidizing equivalents at the OEC. Molecular oxygen and protons are the products of this reaction, which is responsible for the maintenance of an aerobic atmosphere on earth. The OEC is a Mn4CaO5 cluster with nearby bound chloride ions. Sequentially oxidized states of the OEC are termed the S states. The dark-stable state is S1, and oxygen is released on the transition from S3 to S0. Using short laser flashes, individual S states are generated, allowing vibrational spectroscopy to be used to study these different oxidation states of the OEC. In current X-ray crystal structures, hydrogen bonds to water molecules are predicted to form an extensive network around the Mn4CaO5 cluster. In the OEC, four peptide carbonyl groups are linked to the water network, which extends to two Mn-bound and two Ca-bound water molecules. This dissertation discusses a vibrational spectroscopic method that uses these peptide carbonyl frequencies as reporters of solvatochromic changes in the OEC. This technique provides a new, high-resolution method with which to study water and protein dynamics in PSII and other enzymes.

Zugl.: Aachen, Techn. Hochsch., Diss., 2008

Regensburg, Univ., Diss., 2002.

Submitted by Cristhiane Guerra (cristhiane.guerra@gmail.com) on 2017-02-01T12:59:21Z No. of bitstreams: 1 arquivotototal.pdf: 10138565 bytes, checksum: 12bbe7fe2ab950106307c9ed9db462d2 (MD5) / Made available in DSpace on 2017-02-01T12:59:21Z (GMT). No. of bitstreams: 1 arquivotototal.pdf: 10138565 bytes, checksum: 12bbe7fe2ab950106307c9ed9db462d2 (MD5) Previous issue date: 2016-08-12 / This study aimed to prepare a collection of benzylamides to-halogenated derivatives of structurally related benzoic and cinnamic acids by coupling reactions with 4- (chlorine, bromine and fluro) benzylamines using the Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as coupling agent. All compounds prepared were subjected to antimicrobial testing the method broth microdilution, with the antimicrobial control gentamicin, amikacin, norfloxacin, penicillin and nystatin. Also, a study was conducted of quantitative structure-activity relationship (QSAR) using computational software like KNIME v. 3.1.0 and Volsurf v. 1.0.7. The study achieved the preparation of amides 22 and 10 derived ethers and esters of vanillic acid amide, with yields ranging from 29-89%, including 30 novel compounds in the literature and identified by spectroscopic methods such as Infrared and 1H and 13C Magnetic Resonance (NMR) as well as by high resolution mass spectrometry. The antimicrobial evaluation showed that eleven amides showed antifungal activity, an amide presented an antibacterial activity and no amide derivative of vanillic acid showed antimicrobial activity. The QSAR study showed that molecular descriptors related to hydrophobicity, hydrophilicity, pH change, energy interaction and energy difference as DRDRDR, DRDRAC, L4LgS, IW4 and DD2, respectively, influence the antifungal activity of haloamides. It follows that the NR14 amides (Gallic amide) and NR15 (vanillic amide) had considerable Minimum Inhibitory Concentrations (MIC) in antifungal essays, and NR4 (4-methoxycinnamic amide) in the antibacterial test, considered the most active antimicrobial. This result shows that spacer groups as double bond of cinnamic derivatives and addition of hydroxyls in the position para and methoxyl in the meta position on the aromatic ring of the amide enhance the antifungal activity. / O presente trabalho teve como finalidade preparar uma coleção de benzilamidas para-halogenadas derivadas de ácidos cinâmicos e benzoicos estruturalmente relacionadas através de reações de acoplamento com 4-(cloro, fluro e bromo) benzilaminas, utilizando o benzotriazol-1-iloxi-tris-(dimetilamino)-fosfônio (BOP) como agente de acoplamento. Além disso, foram preparados derivados éteres e ésteres da amida do ácido vanílico. Todos os compostos preparados foram submetidos a testes antimicrobianos pelo método microdiluição em caldo, tendo como controle antimicrobiano a gentamicina, a amicacina, o norfloxacino, a penicilina e a nistatina. Também, foi realizado um estudo de relação estrutura-atividade quantitativo (QSAR) utilizando softwares computacionais como o KNIME v. 3.1.0 e Volsurf v. 1.0.7. O estudo realizado resultou na obtenção de 22 amidas e 10 derivados éteres e ésteres da amida do ácido vanílico, com os rendimentos variando entre 29-89%, sendo 30 compostos inéditos na literatura e identificados por métodos espectroscópicos de infravermelho e ressonância magnética de 1H e 13C bem como por espectrometria de massas de alta resolução. A avaliação antimicrobiana demonstrou que onze amidas apresentaram atividade antifúngica, apenas uma apresentou atividade antibacteriana e nenhum derivado da amida do ácido vanílico apresentou atividade antimicrobiana. O estudo QSAR demonstrou que descritores moleculares relacionados à hidrofobicidade, hidrofilia, variação de pH, momentos de interação de energia e diferença de energia como DRDRDR, DRDRAC, L4LgS, IW4 e DD2, respectivamente, influenciam na atividade antifúngica das haloamidas. Conclui-se que as amidas NR14 (amida gálica) e NR15 (amida vanílica) apresentam concentrações inibitórias mínimas antifúngicas consideráveis (CIM), assim como NR4 (amida 4-metoxicinâmica) no ensaio antibacteriano. Esse resultado demonstra que grupos espaçadores como a dupla ligação dos derivados cinâmicos e adição de hidroxilas na posição para e metoxila na posição meta no anel aromático da amida potencializam a atividade antifúngica.

Made available in DSpace on 2015-03-26T13:40:00Z (GMT). No. of bitstreams: 1 texto completo.pdf: 2966468 bytes, checksum: 55a0d05f58805c31796e8b6e80c3cc96 (MD5) Previous issue date: 2013-07-22 / The Macaúba (Acrocomia aculeata) is an oil palm native from the neotropical regions and it is often found in open areas with high solar incidence. Despite being found in regions with sandy soils and a low hydric index, it develops better in locations where there are fertile soils. Acrocomia aculeata is considered a rustic plant and promissory in the extraction and production of combustible oil. The bunches are constituted by globular fruits, drupe type, composed by nearly 20 % epicarp (shell), 40 % mesocarp (pulp), 33 % endocarp (tegument) and 7 % seed (almond). The oil contents are slightly bigger in the pulp (60 %) than in the almond (55 %). The fructification of the Macaúba is supra annual (above 12 months), the fruits maturation is slow and visually undetectable. The epicarp is rigid and it changes its color approximately at 14 weeks after antese (WAA) turning development and fruit maturity really difficult to determine, what is possible to do in other fleshy fruits. Commercialization of plant products such as the fruits, it needs detailed information that allows to estimate the degree of organ development, tissues differentiation, reservoir accumulation and mainly the harvesting point, which will determine perishability and storing period of the product. Generally, all the fleshy fruits show a growing pattern similar. That growing pattern is described by a simple sigmoid behavior, double and sometimes, triples. The description of that growing pattern, influence directly in some agronomic practices such as, irrigation, application of growing regulators, phytosanitary control and critic period of harvesting. This study had as an objective characterize the growing pattern of the constituents parts of the fruit and the reservoir accumulation such as amides, total soluble sugars, (TSS), reducing sugars (RS), no reducing sugars (NRS) and mesocarp oil of the macaúba fruit. The experiment was carried on with adult plants of the native population from the Acaiaca municipality, in the southeast of Minas Gerais Brazil, cataloged as subtropical humid weather according to the climatic classification made by Koppen-Geiger: Cwa. One fruit per bunch was collected one week after the opening of the espata (SAAP) until the natural fall of the fruits at 62 WAA. The opening of the espata was determined based on a visual pattern of the antese of the masculine flower, with an interval between 12-24 hours after opening of the espata (HAAP). For the statistic analyses, the averages of the analyzed variables were used. The experimental design was randomized blocks and for every evaluation a regression equation was estimated. The water content of the fruits reached a maximum pick of 87 % at 8 SAA, posteriorly, it suffered a gradual fall with a minimum value of 23 % of water content at 58 SAA. The growing patterns of the epicarp, endocarp and of the almond were described by a simple sigmoid behavior (an accumulation of dry matter phase), and of the mesocarp by a double sigmoid behavior (two phases of dry matter accumulation). At 6 SAA was possible to separate physically the epicarp, endocarp and the mesocarp which, at this stage, was constituted by: 25 % amide, 10,5 % TSS, 9 % RS and 1,5 % NRS. The oil accumulation in the mesocarp had a linear behavior with 10% oil content at 34 SAA and reaching 55 % at 62 SAA. The oil accumulation in the mesocarp was directly related to an amide content fall. The epicarp and the endocarp reached the biggest dry matter accumulation at 13 SAA and 24 SAA, respectively. The Macaúba fruits obtained the transversal external diameter (TED) maximum (45 mm) at 13 SAA maintaining that constant value until the last evaluation. It was observed that the two first tissues developed were the epicarp and the endocarp, considered structures of protection of the fruit and the seed, respectively. After 13 SAA, began the maturing process of the fruit, which was separated in two phases, physical and chemical. / A Macaúba (Acrocomia aculeata) é uma é uma palmeira nativa das regiões neotropicais e comumente habita áreas abertas e com alta incidência solar. Apesar de ser encontrada em regiões com solos arenosos e baixo índice hídrico, desenvolve-se melhor em locais onde há solos férteis. Acrocomia aculeata e considerada uma planta rustica e promissora na extração e produção de óleo combustível. Os cachos estão constituídos de frutos globosos, do tipo drupa, constituídos por cerca de 20 % de epicarpo (casca), 40 % de mesocarpo (polpa), 33 % de endocarpo (tegumento) e 7 % de semente (amêndoa). Os teores de óleo são ligeiramente maiores na polpa (60 %), em relação à amêndoa (55 %). A frutificação da Macaúba é supra anual (acima de 12 meses), o amadurecimento dos frutos é lento e indetectável visualmente. O epicarpo é duro e muda de coloração aproximadamente às 14 semanas após antese (SAA) tornando difícil determinar o desenvolvimento e maturidade do fruto, o é possível em outros frutos carnosos. A comercialização de produtos vegetais como os frutos, precisa de informações detalhadas que permitam estimar o grão de desenvolvimento do órgão, diferenciação dos tecidos, acumulo de reservas e principalmente o ponto de colheita, o qual determinará a perecibilidade e período de armazenagem do produto. Em geral, todos os frutos carnosos apresentam um padrão de crescimento similar. Esse padrão de crescimento é descrito por um comportamento sigmoide simples, duplo e em alguns casos, triplo. A descrição desse padrão de crescimento, influência diretamente em algumas práticas agronómicas como, irrigação, aplicação de reguladores de crescimento, controle fitossanitário e período crítico de colheita. Este estudo teve como objetivo caracterizar o padrão de crescimento das partes constituintes do fruto e o acúmulo de reservas como amido, açúcares solúveis totais (AST), açúcares redutores (AR), açúcares não redutores (ANR) e óleo do mesocarpo de frutos de macaúba. O experimento foi realizado com plantas adultas de população nativa do município de Acaiaca, região Sudeste de Minas Gerais - Brasil, catalogado como clima subtropical úmido segundo a classificação climática de Koppen-Geiger: Cwa. Coletou-se um fruto por cacho uma semana após abertura da espata (SAAP) até a queda natural dos frutos às 62 SAA. Determinou-se a abertura da espata com base em um padrão visual da antese da flor masculina, intervalo compreendido entre 12-24h horas após abertura da espata (HAAP). Para as análises estatísticas foram usados os valores médios das variáveis analisadas. O delineamento experimental foi em blocos casualizados e para cada avaliação foi estimada a equação de regressão. O teor de água dos frutos atingiu um pico máximo de 87 % às 8 SAA, posteriormente sofreu queda gradual com valor mínimo de 23 % de teor de água às 58 SAA. Os padrões de crescimento do epicarpo, do endocarpo e da amêndoa foram descritos por um comportamento sigmoide simples (uma fase de acúmulo de matéria seca), e do mesocarpo por um comportamento sigmoide duplo (duas fases de acúmulo de matéria seca). Às 6 SAA foi possível separar fisicamente o epicarpo, o endocarpo e o mesocarpo o qual, neste estádio, estava constituído por: 25 % de amido, 10,5 % de AST, 9% de AR e 1,5 % de ANR. O acumulo de óleo no mesocarpo teve um comportamento linear com 10 % de teor de óleo às 34 SAA e atingindo 55 % às 62 SAA. O acúmulo de óleo no mesocarpo esteve diretamente relacionado com a queda no teor de amido. O epicarpo e o endocarpo atingiram o maior acúmulo de massa seca às 13 SAA e 24 SAA, respectivamente. O fruto de macaúba alcançaram o diâmetro externo transversal (DET) máximo (45 mm) às 13 SAA mantendo esse valor constante até a última avalição. Observou-se que os primeiros dois tecidos desenvolvidos foram o epicarpo e o endocarpo, consideradas estruturas de proteção do fruto e da semente, respectivamente. Após 13 SAA, iniciou-se o processo de amadurecimento do fruto, o qual foi separado em duas fases, física e química.

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