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Authors
Abstract(s)
O cancro da próstata é o segundo cancro mais diagnosticado na população masculina, em
todo o mundo. Dado o envelhecimento da população, é uma patologia muitas vezes
associada a outras doenças metabólicas crónicas. Curiosamente, na esmagadora maioria
delas, verifica-se um grande contributo do cluster de diferenciação 36 (CD36), que age
como mediador do influxo de ácidos gordos de cadeia longa, através da membrana celular
e organelos membranares. Esta proteína desempenha alguns papeis no metabolismo
lipidico e em algumas vias de sinalização celular e, quando é sua sobre-expressa, é um
biomarcador no cancro da próstata. Este trabalho de dissertação teve como principais
objetivos o design, síntese, caracterização das propriedades estruturais, atividades
biológicas e aplicabilidades de híbridos de ácidos (tio)barbitúricos e ácidos gordos como
potenciais inibidores do CD36. Assim, foram realizados estudos computacionais para
simular parâmetros farmacocinéticos, druglikness e de inibição do CD36, respetivamente
,por ferramentas online de ADMET, e de docking molecular. Adicionalmente, foram
realizadosestudos in vitro visando a determinação da actividade anti-proliferativa dos
vários compostos e também a inibição do influxo lipidico em células de cancro da próstata,
através do marcador bodipy-C16. Como resultado das tarefas de síntese, foram obtidos 19
compostos e 18 dos seus sais respetivos, apresentando rendimentos entre bons e
excelentes (44 a 92%). No que diz respeito ao docking molecular, observou-se, em geral,
um aumento das energias de ligação com o aumento das cadeias carbonadas. No entanto,
a presença de insaturações levou a que as energias determinadas estagnassem, tendo sido
analisado então as interações em detalhe. Posto isso, foram realizados screennings de
viabilidade celular, e foram seleccionados os compostos para IC50, tendo sido verificado
que, destes, o composto mais promissor era o derivado de ácido araquidónico,
apresentando atividade anti-proliferativa significativa, sendo, simultaneamente, específico
paramas linhas celulares tumorais. O composto mais citotóxico foi o derivado de ácido
esteárico, no entanto, não apresentou seletividade para as células tumorais. Finalmente,
os resultados do screening da inibição de CD36, parecem deixar antever que o derivado de
ácido 10-undecenóico é o mais promissor, apresentando inibição em ambas as linhas
celulares tumorais. Não obtante estes resultados promissores serão necessários trabalhos
adicionais para avaliar futuras otimizações dos compostos sintetizados e ainda possibilitar
uma compreensão completa das potencialidades dos compostos desenvolvidos.
Prostate cancer is the second most diagnosed cancer in the men’s population. Besides the growth of the aged population, it is frequently combined with other chronic metabolic diseases. Curiously, the majority of them have a great contribution of the cluster of differentiation 36 (CD36), that mediates uptake of long-chain fatty acids (FA) through the cell membrane and other membrane-bound organelles. This protein plays some roles in lipid metabolism and cell signaling pathways and this overexpression is watched as a biomarker for prostate cancer. This work aims to promote the design, synthesis and spectroscopic characterization of (thio)barbiturates functionalized with fatty acid’s chains, likewise in silico studies of absorption, distribution, metabolization, excretion and toxicity (ADMET) and molecular docking, and finally, perform in vitro studies of antiproliferative activities, by MTT, and inhibition of FA uptake using bodipy-C16 as well in prostate cancer cells. As a result of synthesis we obtained 18 compounds and the sodium enolates correspondents between good to excellent yields (44-92%). Furthermore, with the molecular docking results, we observed that the binding energies grow proportionally with the size of the chain FA, but decrease whit isomerization trans, and more than 2 unsaturation. Considering the antiproliferative studies, the initial screening showed that the cytotoxicity of prostate cancer cells increased with the size of the chain’s FA. However, the selectivity for tumoral cellsgrows with the presence of unsaturation cis. The calculations of the half of the maximum inhibitory concentration (IC50) determined that the most potent antiproliferative compound was the arachidonic acid derivative and was also the most selective. Finally, the bodipy-C16 assay shows that all synthesized compounds have inhibitory activity and in this way the most promising one is the derivative of 10-undecenoic acid. However, more biological studies in this context will be required, in order to elucidate the potential structural optimization of molecules and make a full overview of the pathways favorable to these findings.
Prostate cancer is the second most diagnosed cancer in the men’s population. Besides the growth of the aged population, it is frequently combined with other chronic metabolic diseases. Curiously, the majority of them have a great contribution of the cluster of differentiation 36 (CD36), that mediates uptake of long-chain fatty acids (FA) through the cell membrane and other membrane-bound organelles. This protein plays some roles in lipid metabolism and cell signaling pathways and this overexpression is watched as a biomarker for prostate cancer. This work aims to promote the design, synthesis and spectroscopic characterization of (thio)barbiturates functionalized with fatty acid’s chains, likewise in silico studies of absorption, distribution, metabolization, excretion and toxicity (ADMET) and molecular docking, and finally, perform in vitro studies of antiproliferative activities, by MTT, and inhibition of FA uptake using bodipy-C16 as well in prostate cancer cells. As a result of synthesis we obtained 18 compounds and the sodium enolates correspondents between good to excellent yields (44-92%). Furthermore, with the molecular docking results, we observed that the binding energies grow proportionally with the size of the chain FA, but decrease whit isomerization trans, and more than 2 unsaturation. Considering the antiproliferative studies, the initial screening showed that the cytotoxicity of prostate cancer cells increased with the size of the chain’s FA. However, the selectivity for tumoral cellsgrows with the presence of unsaturation cis. The calculations of the half of the maximum inhibitory concentration (IC50) determined that the most potent antiproliferative compound was the arachidonic acid derivative and was also the most selective. Finally, the bodipy-C16 assay shows that all synthesized compounds have inhibitory activity and in this way the most promising one is the derivative of 10-undecenoic acid. However, more biological studies in this context will be required, in order to elucidate the potential structural optimization of molecules and make a full overview of the pathways favorable to these findings.
Description
Keywords
Cancro da Próstata Estudos Computacionais Inibição do Cd36 Síntese Química Viabilidade Celular