Flavonoids with Potential Anti-Inflammatory Activity: in Vitro Structure/Activity Studies of Their Effects in Pro- Inflammatory Signalling Systems

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Flavonoids with Potential Anti-Inflammatory Activity: in Vitro Structure/Activity Studies of Their Effects in Pro- Inflammatory Signalling Systems Daniela Sofia Almeida Ribeiro Flavonoids with potential anti-inflammatory activity: in vitro structure/activity studies of their effects in pro- inflammatory signalling systems Tese do 3º Ciclo de Estudos Conducente ao Grau de Doutoramento em Ciências Farmacêuticas na Especialidade de Química Farmacêutica e Medicinal Trabalho realizado sob a orientação do Professor Doutor José Luís Fontes da Costa Lima e da Professora Doutora Eduarda das Graças Rodrigues Fernandes Outubro de 2014 iii É autorizada a reprodução integral desta tese apenas para efeitos de investigação, mediante declaração escrita do interessado, que a tal se compromete. Assinatura do autor, iv Agradecimentos São tantas e tão importantes as pessoas que se têm cruzado comigo ao longo deste meu percurso. Umas por um período de tempo mais prolongado, outras, mais curto, mas todas foram deixando a sua marca neste meu caminho pela vida, e, em especial, nesta etapa tão importante para mim, o doutoramento. É uma tarefa muito difícil, se não impossível, agradecer a todos aqueles que de alguma forma contribuíram e estiveram presentes nesta minha etapa de vida, mas existem algumas pessoas a quem eu não poderia deixar de agradecer: Ao Professor Doutor José Costa Lima, por inúmeras razões. Por me ter recebido de braços abertos, com a alegria que o caracteriza, no seu gabinete, ainda no antigo Departamento de Química-Física, e me ter dito, que, de forma geral, e embora eu não estivesse certa de que queria a investigação na minha vida, todas as pessoas que entravam naquele laboratório acabavam por adorar o que faziam e por ficar. Eu não fui exceção! E, como sempre, o Professor tinha razão! E aqui estou, agora no novo Laboratório de Química Aplicada. Quero agradecer por ter aceitado ser meu orientador e por me ter acompanhado durante todo este percurso do doutoramento, e por todos os ensinamentos que me tem transmitido. Agradeço pelo seu empenho e dedicação na gestão e no melhoramento deste tão grande grupo de investigação, e por estar sempre atento a todas as nossas necessidades, que se esforça sempre por suprir. Por fim, quero agradecer por permitir e tornar possíveis todas as deslocações e participações em congressos do “trem da alegria”, sem o qual este doutoramento não teria sido a mesma coisa, com episódios e peripécias que irão para sempre ficar na minha memória. À Professora Doutora Eduarda Fernandes, por tudo! Por me ter acompanhado sempre desde os meus primeiros passos na investigação, por me ter incutido o gosto pelo que faço hoje, por me ter incentivado, apoiado e ajudado no ingresso em doutoramento. São tantas as palavras e tão poucas para lhe agradecer… Agradecer por estar sempre, reforço, sempre, disponível para me guiar e orientar desde o primeiro dia de doutoramento. Por estar sempre presente, por podermos discutir o trabalho em tempo real, todos os dias, sem exceção. Não posso deixar de destacar o seu valor enquanto profissional, com exímias provas dadas no meio científico e académico, com um percurso profissional brilhante. Agradeço a transmissão do seu tão vasto conhecimento, a partilha daquilo que melhor conhece e sabe fazer. Agradeço as nossas conversas sobre o trabalho, mas não só, enquanto amiga também. São incontáveis as suas palavras de v apoio e de força nos momentos de mais dificuldade. E porque a nossa vida vai tendo altos e baixos, agradecer o esforço por nunca ter deixado de estar presente. Salientar também o seu sentido de humor, porque os momentos de alegria e ‘risota’ também foram muitos, e o que seria das nossas vidas sem eles… Por fim, destacar a excelente companheira de viagem, passamos momentos muito bons, de muito boa disposição, que ficarão para sempre na minha memória. Ser-lhe-ei eternamente grata…. À Professora Doutora Graça Porto, do Hospital Geral de Santo António, a sua disponibilidade e preciosa contribuição para a realização deste trabalho. Ao Professor Doutor Artur Silva, da Universidade de Aveiro, pela sua contribuição na síntese de alguns compostos necessários à realização de alguns trabalhos experimentais e pela disponibilidade sempre demonstrada. À Professora Doutora Maria Manuel, da Universidade Nova de Lisboa, por me ter recebido tão bem em Lisboa, e por me ter dado todo o apoio necessário nos trabalhos realizados com recurso à RMN. Ao Professor Doutor Félix Carvalho agradeço o conhecimento transmitido, o, muitas vezes precioso, brainstorming, que tanto contribuíram para a evolução do trabalho. Agradeço, também, o facto de me ter proporcionado a oportunidade de utilizar equipamentos do Laboratório de Toxicologia, que foram indispensáveis para a execução de alguns trabalhos laboratoriais. À minha querida Marisa, colega de laboratório de sempre, amiga. Obrigada! Agradecer por me ter recebido tão bem, desde o primeiro dia em que pisei o laboratório. Por me ter ensinado, e tão bem, tudo, desde o início. Por estar sempre presente, por estar sempre disponível para discutir o trabalho comigo, por ter sempre uma opinião válida e assertiva, porque o seu conhecimento e valor científico estão mais que comprovados. Agradecer as nossas aventuras de congressos, as nossas risadas, os nossos momentos de choro, às vezes de tristeza, outras de alegria. Agradecer a confiança que depositaste e depositas em mim. Levar-te-ei sempre comigo para a vida. Obrigada. A todos os meus colegas da FRAU (Free Radicals and Antioxidants Unit): Renan Chisté, meu querido amigo Brasileiro, que será, para sempre, lembrado como fundador do “cantinho brasileiro” no laboratório; Diana Couto, que percorreu e percorre este caminho de doutoramento comigo, agradecer a camaradagem; a todos os outros elementos, mais fixos, Alessandra Ribeiro e Clementina Santos agradecer o companheirismo e os muitos vi bons momentos passados juntos; aos elementos que vão passando períodos mais curtos na FRAU, o meu agradecimento, porque todos contribuem para a nossa aprendizagem e para manter e melhorar o excelente ambiente de trabalho. Agradeço a todos os Professores e colegas do Laboratório de Química Aplicada que, de uma forma directa ou indirecta, contribuíram, ou auxiliaram na elaboração do presente estudo, nomeadamente, com a sua generosa dádiva de sangue. Para não correr o risco de não enumerar algum, não vou identificar ninguém, aqueles a quem este agradecimento se dirige sabê-lo-ão. À Engenheira Manuela Barros e à Patrícia Monteiro agradeço a simpatia, a disponibilidade, a ajuda dispensada e o esforço por sempre satisfazerem os meus pedidos. Aos membros do Laboratório de Toxicologia, agradeço a simpatia e a disponibilidade sempre demonstrada e a ajuda na utilização dos equipamentos do Laboratório de Toxicologia, que foram indispensáveis para a execução de alguns trabalhos laboratoriais. Aos meus amigos de sempre, e sempre presentes, Susana, Pedro, Alice, André, Inês e Rui fica aqui o meu agradecimento por me acompanharem há já alguns anos, por partilharem comigo as suas vidas e por me darem o privilégio de participar nelas. Em especial à Susana, amiga de há mesmo muitos anos, pela partilha aberta e sincera de opiniões, por seguirmos atentamente as caminhadas da vida e de doutoramento uma da outra, e nestes últimos quatro anos, pelos nossos longos e ‘telepáticos’ emails trocados, porque nem sempre o tempo disponível é muito para estarmos com os nossos amigos “ao vivo”. À Patrícia Monteiro e à Joana Fonseca, amigas não de sempre, mas que estão sempre presentes, e estarão, no meu dia-a-dia, agradecer todos os momentos passados, os mais marcantes, os mais tristes, mas também os mais divertidos, e estes sim foram muitos, mesmo muitos. Por último, às pessoas mais importantes da minha vida, os meus pais. Sem eles nada disto seria possível. Em especial nesta etapa da minha vida agradecer a vossa disponibilidade, as boleias tardias, a vossa compreensão e respeito por aquilo que faço. Agradecer o vosso apoio incondicional, desde sempre. Agradecer o esforço que fizeram e vii fazem para me permitir seguir os meus sonhos, seja qual for o caminho que eu deseje traçar. Agradeço ainda à Faculdade de Farmácia da Universidade do Porto o facto de me ter aceitado como estudante de Doutoramento. À FCT agradeço a bolsa de doutoramento que me foi concedida (SFRH/BD/72966/2010) e todo o apoio financeiro, no âmbito do “QREN e POPH e Tipologia 4.1 e Formação Avançada”, co-financiado pelo FSE e pelos fundos nacionais do MCTES. viii Abstract The term inflammation comprises the physiologic response of the organism to unchecked tissue damage from infection or injury. In spite of being a body’s natural defence, the inflammatory response may contribute to the development of pathologic processes when the anti-inflammatory defences of the organism are not enough to contain and antagonize the deleterious activities of the overproduced pro-inflammatory mediators. Chronic inflammatory diseases, like rheumatoid arthritis, Crohn’s disease, Alzheimer’s disease, diabetes, among others, are responsible for the permanent affliction, disability, and, many times, premature death of millions of patients. They constitute a heavy burden for modern society. Unfortunately, the traditional steroidal or non-steroidal anti-inflammatory therapies are either not enough or associated with too many side effects. New therapeutic approaches are urgently required – more efficient and safer new drugs. In recent years, flavonoids have been associated with various health benefits, including its anti-inflammatory effects. These properties associated with their ubiquitous distribution in nature, and their presence in the great majority of foods, as part of our daily diet, made flavonoids great value-added molecules. Taking in account these potential anti- inflammatory properties, flavonoids started to be considered a valuable alternative to modulate and prevent inflammatory processes; and moreover, to be the base to the synthesis of more potent and efficient anti-inflammatory drugs. The work developed in this PhD thesis intends to extend and rationalize the current knowledge on the alleged anti- inflammatory properties of flavonoids by elucidating the mechanism of action related with their structure (structure-activity relationship).
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