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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2019.tde-04092019-142347
Document
Author
Full name
María Teresa Páez González
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Emery, Flavio da Silva (President)
Clososki, Giuliano Cesar
Ito, Amando Siuiti
Lopez, Fabian Orozco
Okano, Laura Tiemi
Title in Portuguese
Síntese de hibrido Ritonavir/Lopinavir como inhibidor de protease do vírus HIV-1 e estudo do núcleo 1,3,5-triazina em busca de derivados com atividade biológica
Keywords in Portuguese
Antiretroviral
BODPIY
Câncer
HIV
Triazinas
Abstract in Portuguese
Diversas pesquisas foram realizadas ao longo das últimas décadas, levando ao desenvolvimento de um grande número de fármacos para o tratamento de doenças como HIV, câncer e outros vírus. No entanto, a administração a longo prazo destes fármacos está associada à geração de síndromes, à aparição de novas doenças e abandono do tratamento. Nesse sentido, e com o intuito de buscar moléculas menos prejudiciais, decidimos realizar o estudo de dois tipos de possíveis novos fármacos. O primeiro deles a partir do estudo metodológico de intermediários provenientes de aminoácidos modificados, visando a obtenção de um composto híbrido que poderá atuar como inibidor de protease do vírus do HIV-1, e o segundo a partir do estudo de reatividade do anel 1,3,5-triazina, partindo do cloreto cianúrico e do analise de reações com diversos nucleófilos. Os nossos resultados mostraram que no caso da síntese do híbrido, a dificuldade na purificação dos compostos impediu obter todos os intermediários propostos pelo que a molécula final não foi obtida. Os resultados das triazinas foram mais promissórios, uma vez que a partir dos estudos teóricos foram determinadas possíveis moléculas com atividade biológica, foi determinado que existem mais condições a serem controladas nas reações do cloreto cianúrico. Os derivados propostos foram sintetizados e a atividade biológica foi avaliada. Os resultados biológicos mostraram existe interação molecular das triazinas sintetizadas com diferentes tipos de células de câncer. Finalmente, como parte de nossos estudos de reatividade de triazinas, foram sintetizados derivados de triazina-BODIPY, onde observamos que a extensão da conjugação do anel 1,3,5-triazina, modifica as características fotofísicas do fluoroforo. Todos estes estudos permitem pensar nas triazinas como núcleos interessantes para estudos posteriores
Title in English
Synthesis of Ritonavir / Lopinavir hybrid as a protease inhibitor of hiv-1 virus and study of 1,3,5-triazine nucleus in search of derivatives with biological activity
Keywords in English
Antiretroviral
BODPIY
Cancer
HIV
Triazines
Abstract in English
A vastly quantity of scientific research were made through the last decade on the development of a great number of drugs to treat complex diseases like HIV or cancer. However, the long-term treatment with these drugs is actually associated with appearance of idiopathic syndromes that carry to stop the treatment. In this sense, we sought to perform a study of two novel promissory drugs. The first one was performed from a methodological study of intermediaries came from modified amino acids to obtain a hybrid compound that would act as a protease inhibitor against HIV-1. The second one was performed from the study of 1,3,5-triazine ring reactivity, starting from cyanuric chloride and the analysis of reactions with diverse nucleophiles. Our results showed that for the hybrid synthesis, a difficulty on purification impede to obtain all the intermediaries so that molecule was not obtained. The results for triazines, were promissory due to theoretical studies let us to determine possible biological activity and was observed that there are more conditions that must be evaluated on cyanuric chloride reactions. In addition, the proposed derivatives were synthetized and the biological activity was assessed. Biological outcome showed that triazine have a direct interaction with different cultured cancer cells. Finally, as a part of our reactivity studies about triazines we synthetized triazine-BODIPY derivatives in which, we observed that the extension of the conjugation for 1,3,5 triazine ring modified photophisical characteristics of the fluorophore. Thus, our results suggested that triazines could have promissory properties that must be explore in further studies
 
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Publishing Date
2019-11-26
 
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