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Desenvolvimento de híbridos de triazenos anti-tumorais
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Resumo(s)
As doenças cancerígenas são apresentadas como principais causas de morte por todo o mundo. Apesar da evolução da terapêutica nos últimos anos, o Glioblastoma Multiforme e o melanoma metastático são tumores agressivos e de rápida progressão, e por isso, a terapêutica com quimioterapia continua a apresentar reduzida taxa de sobrevivência. O Temozolomide (TMZ), um pró-fármaco com estrutura de triazeno, responsável pela sua atividade anti-cancerígena é utilizado para o tratamento destes tumores. Apesar de apresentar propriedades farmacocinéticas favoráveis, tem sido associado ao aparecimento de resistência. A associação de outros fármacos com o TMZ continua sem demonstrar a eficácia desejada. A síntese de uma molécula com dois farmacóforos com mecanismos anti-tumorais diferentes tem demonstrado ser uma possível alternativa ao TMZ. Estes fármacos são denominados de fármacos Híbridos. Estes híbridos têm na sua constituição um agente metilante de DNA, Monometiltriazeno (MMT), e um ácido carboxílico de cadeia curta ,βinsaturado com função de inibidor de Histona Deacetilases (HDACi). O ácido cinâmico e alguns derivados têm sido estudados pelas suas propriedades farmacológicas, incluindo como anti-tumoral. Em estudos anteriores o ácido cinâmico demonstrou atividade como HDACi. Diversos métodos têm sido usados para a síntese deste tipo de compostos, com o objetivo de melhorar o rendimento e a rapidez da obtenção de produto, nomeadamente com a utilização de agentes de ativação de ácidos carboxílicos. O design de fármacos compreende atualmente um vasto conjunto de estudos que tem por base não só a análise do seu potencial terapêutico, como também dos seus possíveis mecanismos de toxicidade. Os compostos Híbridos derivados de ácidos carboxílicos ,βinsaturados, devido à sua estrutura, apresentam capacidade de funcionarem como aceitadores de Michael e por isso serem potencialmente tóxicos. No presente trabalho foram sintetizados compostos Híbridos constituídos por monometiltriazeno e ácido trans-cinâmico, recorrendo a um método de síntese que promovesse mais facilmente a formação da ligação amida, bem como a sua caracterização estrutural, e a ação anti-tumoral.
Nowadays, cancer diseases are one of the main causes of death around the world. In spite of the therapeutics advances on the last few years, Glioblastoma Multiform and metastatic melanoma are still very aggressive tumours and with rapid progression. Due to these characteristics, the current chemotherapy treatments still present a low survival rate. Temozolomide (TMZ), a pro-drug that has a triazene structure responsible for its anticancer activity, is used as treatment for these type of tumours. Although it presents favourable pharmacokinetic properties, it has been associated to the appearance of mechanisms of resistance. The association of TMZ with other drugs still doesn´t show to be efficient enough. The synthesis of a molecule with two pharmacophores with different anti-tumour mechanisms has been shown to be a possible alternative to TMZ. These drugs, called Hybrid drugs have in their structures a DNA methylating agent, Monomethyl triazene (MMT), and a small chain ,β-unsaturated carboxylic acid that acts has a Histone Deacetilase inhibitor (HDACi). Several methods have been used for the synthesis of this kind of compounds, aiming to improve some aspects including: yield and the time spent to obtain the final product, like the use of carboxylic acids activating agents. Drug design includes a broad set of studies based not only in the analysis of their therapeutic potential but as well as their possible toxicity mechanisms. Hybrid compounds derivate from an ,β-unsaturated carboxylic acids present, due to their structure, the ability to function as Michael acceptors and therefore potentially be responsible for some mechanisms of toxicity. In this work project there were synthesised Hybrid compounds constituted by monomethyl triazene and trans-cinnamic acid moieties, with the use of a synthesis method that could easily promote the amid bond formation. The compounds synthesised were then studied and analysed concerning their structural characterization and anti-tumor mechanism.
Nowadays, cancer diseases are one of the main causes of death around the world. In spite of the therapeutics advances on the last few years, Glioblastoma Multiform and metastatic melanoma are still very aggressive tumours and with rapid progression. Due to these characteristics, the current chemotherapy treatments still present a low survival rate. Temozolomide (TMZ), a pro-drug that has a triazene structure responsible for its anticancer activity, is used as treatment for these type of tumours. Although it presents favourable pharmacokinetic properties, it has been associated to the appearance of mechanisms of resistance. The association of TMZ with other drugs still doesn´t show to be efficient enough. The synthesis of a molecule with two pharmacophores with different anti-tumour mechanisms has been shown to be a possible alternative to TMZ. These drugs, called Hybrid drugs have in their structures a DNA methylating agent, Monomethyl triazene (MMT), and a small chain ,β-unsaturated carboxylic acid that acts has a Histone Deacetilase inhibitor (HDACi). Several methods have been used for the synthesis of this kind of compounds, aiming to improve some aspects including: yield and the time spent to obtain the final product, like the use of carboxylic acids activating agents. Drug design includes a broad set of studies based not only in the analysis of their therapeutic potential but as well as their possible toxicity mechanisms. Hybrid compounds derivate from an ,β-unsaturated carboxylic acids present, due to their structure, the ability to function as Michael acceptors and therefore potentially be responsible for some mechanisms of toxicity. In this work project there were synthesised Hybrid compounds constituted by monomethyl triazene and trans-cinnamic acid moieties, with the use of a synthesis method that could easily promote the amid bond formation. The compounds synthesised were then studied and analysed concerning their structural characterization and anti-tumor mechanism.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Palavras-chave
Cancro TMZ Fármacos híbridos Ácido cinâmico Mestrado Integrado - 2019