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Synthesis of hybrid compounds for colon cancer treatment
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Resumo(s)
O cancro do colón é o terceiro mais comum em todo o mundo e o segundo no que diz
respeito ao número de mortes por cancro a nível mundial. O seu desenvolvimento
deve-se a alterações no epitélio colónico normal, com formação de pólipos
adenomatosos que podem proliferar, aumentar o seu tamanho e levar a mutações
genéticas e epigenéticas que se acumulam ao longo do tempo.
As principais opções terapêuticas são cirurgia, radioterapia, quimioterapia à base de 5-
fluorouracilo ou capecitabina e terapia direcionada. A quimioterapia é a opção mais
utilizada e explorada para o tratamento do cancro do cólon metastático. O 5-
Fluorouracilo é um pilar vital neste tratamento, sendo este responsável por danificar
DNA e RNA através da sua incorporação incorreta. No entanto, devido aos seus
efeitos secundários e ao desenvolvimento de resistência ao medicamento, há uma
grande necessidade de descoberta de outras opções mais eficazes. Simultaneamente,
outro grupo de moléculas, os triazenos, também são conhecidos pelas suas
propriedades anticancerígenas. Este grupo de compostos tem sido amplamente
estudado para a obtenção de novos derivados, como pró-fármacos ou híbridos,
apresentando um vasto leque de estruturas e propriedades químicas próprias para o
tratamento de diversos tipos de tumores.
Neste trabalho, explora-se a possibilidade de unir o 5-Fluorouracilo e um triazeno,
usando um espaçador, com o objetivo de sintetizar moléculas híbridas com maior
potência, menos efeitos secundários e capaz de superar a resistência aos múltiplos
medicamentos. Pretende-se sintetizar uma biblioteca de compostos híbridos, variando
a estrutura do triazeno e do espaçador. Os compostos serão depois testados em
linhas celulares de cancro de colón, para escolher o melhor que possa ser
nanoformulado e validado em modelos animais apropriados.
Desta forma, foi possível sintetizar um novo híbrido. Adicionalmente, foram obtidos 3
novos derivados do 5-Fluorouracilo com uma arquitetura diferente do que inicialmente
planeada. Os compostos obtidos foram caracterizados por métodos
espetrofotométricos. Um dos derivados do 5-Fluorouracilo foi testado em linhas
celulares de cancro de colón, apresentando atividade citotóxica na linha de cancro de
colón murina, CT-26 (IC50 = 50 µM).
Colon cancer is the third most common around the world and the second leading cause of cancer related-deaths worldwide. Its development is due to changes in normal colonic epithelium, with formation of adenomatous polyps that might proliferate, increase in their dimension and lead to genetic and epigenetic mutations that accumulate over time. The therapeutic options are surgery, radiation; chemotherapy based on 5-Fluorouracil or capecitabine and targeted therapy. Chemotherapy is the most utilized and explored option for treating metastatic colon cancer. 5-Fluorouracil is a vital pilar in this treatment, being responsible for RNA and DNA damage through their misincorporation. However, due to its side effects and its drug resistance development, there is a significant need to discover more effective alternatives. Simultaneously, another group of molecules, the triazenes, has also been reported to exhibit therapeutic activity, including anticancer properties. This group has been extensively developed to obtain new derivatives, either alone, as prodrugs, combi-molecules, or hybrids, offering a wide range of structures and particular chemical properties suitable for treating various types of tumors. In this work, the possibility of combining these two molecules, 5-Fluorouracil and a triazene, using a linker, is explored, aiming to synthesise hybrid molecules. In order to obtain a compound with higher potency, fewer side effects and able to overcome multidrug resistance, the intention is to generate a small library of hybrid compounds. Compounds were after evaluated in colon cancer cell lines and the best compound will be nanoformulated and validated in appropriated murine models. As a result, a new hybrid was successfully synthesised. Additionally, three new derivatives of 5-fluorouracil with a different architecture than initially expected were obtained. The compounds were characterised by spectroscopic methods. One of the derivatives of 5-fluorouracil was tested in colon cancer cell lines, showing cytotoxic activity against the murine colon cancer cell line, CT-26 (IC50 = 50 µM).
Colon cancer is the third most common around the world and the second leading cause of cancer related-deaths worldwide. Its development is due to changes in normal colonic epithelium, with formation of adenomatous polyps that might proliferate, increase in their dimension and lead to genetic and epigenetic mutations that accumulate over time. The therapeutic options are surgery, radiation; chemotherapy based on 5-Fluorouracil or capecitabine and targeted therapy. Chemotherapy is the most utilized and explored option for treating metastatic colon cancer. 5-Fluorouracil is a vital pilar in this treatment, being responsible for RNA and DNA damage through their misincorporation. However, due to its side effects and its drug resistance development, there is a significant need to discover more effective alternatives. Simultaneously, another group of molecules, the triazenes, has also been reported to exhibit therapeutic activity, including anticancer properties. This group has been extensively developed to obtain new derivatives, either alone, as prodrugs, combi-molecules, or hybrids, offering a wide range of structures and particular chemical properties suitable for treating various types of tumors. In this work, the possibility of combining these two molecules, 5-Fluorouracil and a triazene, using a linker, is explored, aiming to synthesise hybrid molecules. In order to obtain a compound with higher potency, fewer side effects and able to overcome multidrug resistance, the intention is to generate a small library of hybrid compounds. Compounds were after evaluated in colon cancer cell lines and the best compound will be nanoformulated and validated in appropriated murine models. As a result, a new hybrid was successfully synthesised. Additionally, three new derivatives of 5-fluorouracil with a different architecture than initially expected were obtained. The compounds were characterised by spectroscopic methods. One of the derivatives of 5-fluorouracil was tested in colon cancer cell lines, showing cytotoxic activity against the murine colon cancer cell line, CT-26 (IC50 = 50 µM).
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024, Universidade de Lisboa, Faculdade de Farmácia
Palavras-chave
5- Fluorouracil Triazenes Metastatic colon cancer Hybrid molecules Synthesis Mestrado Integrado - 2024