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Abstract(s)
O conhecimento que temos sobre o cancro tem evoluído, desde a sua primeira definição por Hipócrates, em 400 AC. Atualmente, o cancro é compreendido a um nível molecular, o que permite o desenvolvimento de meios de diagnóstico e terapêuticas. Apesar de muito se conhecer, problemas com os atuais métodos de diagnóstico e terapêuticas ainda subsistem. Um destes problemas é a falta de seletividade dos fármacos ou sondas utilizadas, o que frequentemente leva a diagnósticos ou tratamentos ineficazes, ao aparecimento de efeitos sistémicos e ao desenvolvimento de resistência aos fármacos. Para combater estes problemas diversas estratégias têm sido desenvolvidas. Uma destas estratégias é a fotofarmacologia, a qual permite um controlo preciso e seletivo de onde e quando é libertado um fármaco ou sonda. Outra estratégia é o desenvolvimento de pró-fármacos que apenas possam ser ativados na presença de um estímulo (pró-fármacos auto-imolativos) fornecido pelas células cancerígenas ou pelo seu ambiente. Com base na literatura, o grupo 6-nitroveratrilo suscitou interesse por permitir explorar ambas as estratégias ao funcionar tanto como grupo fotoprotetor como grupo auto-imolativo. Neste trabalho, primeiro foi explorada a fotofarmacologia, ao ser sintetizado um composto que liberta um grupo fluorescente após ser exposto a luz UV de um comprimento de onda específico (funcionando como sonda). A sua síntese e purificação foram otimizadas, e o composto foi caracterizado (espectroscopia de ressonância magnética nuclear de hidrogénio e carbono, espetroscopia ultravioleta, e ponto de fusão). Foi realizado um estudo de fotoativação deste composto, sendo demonstrada a libertação do grupo fluorescente após exposição à luz UV. Em segundo lugar, sabendo que o grupo era capaz de libertar a função acoplada, foram explorados os pró-fármacos auto-imolativos. Foram sintetizados conjugados de arilmonometiltriazenos (espécies ativas de medicamentos usados no cancro) com o grupo 6-nitroveratrilo e foram feitas tentativas de otimizar a sua síntese e purificação (ao testar diferentes técnicas de purificação e misturas de eluentes). Um destes conjugados foi sintetizado com sucesso. Durante estas tentativas, ao usarmos a espetroscopia de massa para analisar os produtos da reação, obtivemos informação sobre os compostos que se formam durante a reação e sobre a possível influência do substituinte do arilmonometiltriazeno (no anel aromático) no produto da reação.
Knowledge about cancer has evolved since its first denomination by Hippocrates around 400 BC. Nowadays, cancer is understood even at the molecular level which allows for the development of therapies and diagnosis tools. Even tough so much is known, there are still problems with the current treatments and diagnosis tools. One of these problems is the lack of selectivity to the cancer cells of the used drugs or probes, which often leads to ineffective diagnosis or treatment, to the appearance of systemic effects and to the development of drug resistance. To overcome these problems, scientists have long been developing strategies. Photopharmacology is one of these strategies, which allows the precise and selective control of when and where a drug or probe is released. Another strategy is the development of prodrugs which can only be activated in the presence of a stimulus (self-immolative prodrugs) provided by the cancer cells or their environment. Searching the literature, we found that the 6-nitroveratryl group works both as a photoprotecting group and a self-immolative moiety, being suitable to explore both strategies. In this work, the photopharmacology strategy was first explored, by synthesizing a compound which releases a fluorescent moiety after being exposed to UV light of a specific wavelength (functioning as probe). Its synthesis and purification were optimized, and the compound was characterized (Hydrogen and Carbon nuclear magnetic resonance spectroscopy, UV spectroscopy, and melting point). A photoactivation study of this compound was executed and showed the release of the fluorescent moiety after the exposure of the compound to UV light of a specific wavelength. Secondly, knowing that the 6-nitroveratryl group was suitable for the release of a linked moiety, we aimed at the self-immolative prodrug strategy. Conjugates of arylmonomethyltriazenes (active species of marketed cancer drugs) with the 6-nitroveratryl group were synthesized and we attempted to optimize their synthesis and purification (by testing different eluent mixtures and purification techniques). We were able to successfully synthesize and isolate one conjugate. During these attempts, by utilizing mass spectroscopy to analyse the reaction products we were able to obtain insights about the compounds that formed during the reaction and the possible influence of the substituent of the arylmomomethyltriazene (in the aromatic ring) in the product of the reaction.
Knowledge about cancer has evolved since its first denomination by Hippocrates around 400 BC. Nowadays, cancer is understood even at the molecular level which allows for the development of therapies and diagnosis tools. Even tough so much is known, there are still problems with the current treatments and diagnosis tools. One of these problems is the lack of selectivity to the cancer cells of the used drugs or probes, which often leads to ineffective diagnosis or treatment, to the appearance of systemic effects and to the development of drug resistance. To overcome these problems, scientists have long been developing strategies. Photopharmacology is one of these strategies, which allows the precise and selective control of when and where a drug or probe is released. Another strategy is the development of prodrugs which can only be activated in the presence of a stimulus (self-immolative prodrugs) provided by the cancer cells or their environment. Searching the literature, we found that the 6-nitroveratryl group works both as a photoprotecting group and a self-immolative moiety, being suitable to explore both strategies. In this work, the photopharmacology strategy was first explored, by synthesizing a compound which releases a fluorescent moiety after being exposed to UV light of a specific wavelength (functioning as probe). Its synthesis and purification were optimized, and the compound was characterized (Hydrogen and Carbon nuclear magnetic resonance spectroscopy, UV spectroscopy, and melting point). A photoactivation study of this compound was executed and showed the release of the fluorescent moiety after the exposure of the compound to UV light of a specific wavelength. Secondly, knowing that the 6-nitroveratryl group was suitable for the release of a linked moiety, we aimed at the self-immolative prodrug strategy. Conjugates of arylmonomethyltriazenes (active species of marketed cancer drugs) with the 6-nitroveratryl group were synthesized and we attempted to optimize their synthesis and purification (by testing different eluent mixtures and purification techniques). We were able to successfully synthesize and isolate one conjugate. During these attempts, by utilizing mass spectroscopy to analyse the reaction products we were able to obtain insights about the compounds that formed during the reaction and the possible influence of the substituent of the arylmomomethyltriazene (in the aromatic ring) in the product of the reaction.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Cancro Triazenos Pró-fármacos Fotofarmacologia Sondas Mestrado integrado - 2020