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Abstract(s)
O cancro é uma doença com elevada mortalidade e morbilidade, tem tido um severo impacto socioeconómico. Apesar dos grandes avanços científicos, os fármacos usados atualmente no tratamento de tumores malignos têm uma eficácia geralmente baixa e efeitos secundários severos, o que tem estimulado a investigação de novos fármacos nas últimas décadas.
Os ácidos biliares têm sido vastamente utilizados na síntese química para desenvolvimento de novos fármacos, principalmente devido à elevada estabilidade da estrutura base do esteroide, reatividade das cadeias laterais, baixo custo e alta disponibilidade. Uma estratégia relevante neste âmbito consiste no desenvolvimento de moléculas que possam combinar a estrutura do esteroide com poliaminas, que possuam potencial ação anticancerígena, bem como também com capacidade de interagir e estabilizar o G-quadruplex. De facto, as poliaminas têm o potencial para participar em interações eletrostáticas entre a sua carga positiva ao pH fisiológico e a estrutura polianiónica do DNA, favorecendo as bioatividades pretendidas.
Assim, neste trabalho, a síntese química consistiu, primeiro, na acilação do ácido litocólico ou desoxicólico com o anidrido succínico, seguido do acoplamento com diferentes poliaminas usando o DCC como ativador desta transformação. Posteriormente, os compostos foram avaliados quanto à sua ação antiproliferativa através do ensaio MTT nas linhas celulares LNCaP, MCF-7, T-47D, U87 e NHDF e por citometria de fluxo (em células MCF-7). A capacidade do ligando interagir com o G-quadruplex e a sua estabilização foi avaliada por dicroísmo circular com uma sequência telomérica de G-quadruplex.
Os resultados deste estudo mostraram que os derivados do ácido desoxicólico, destacando-se o produto 7, que parece ter seletividade para tumores hormono-dependentes. No entanto, esta ação não se correlaciona com a estabilização do G-quadruplex telomérico, uma vez que tem fraco efeito estabilizador desta sequência, com tendência para estabilizar a topologia paralela. Os estudos por citometria de fluxo revelam a hipótese de que este composto possa promover a apoptose das células MCF-7.
Em conclusão, foi possível sintetizar novos compostos, sendo que um deles, o produto 7, parece ter algum potencial para continuar a ser estudado e pode ter interesse na criação de novos análogos melhorados, com potencial farmacológico como agentes anticancerígenos.
Cancer is a disease with high morbidity and mortality, and with a severe socio-economic impact. Despite the enormous scientific advances, the drugs currently used in the treatment of malignant tumors have low efficacy and severe side effects, so this have stimulated research in the development of new drugs in this area over the past decades. Bile acids have been widely applied in synthetic chemistry mainly due to their enantiomeric purity, high stability of the steroid nucleus, reactivity of the side chain groups, low cost and ready availability. A relevant strategy consists in development of molecules that combine its core base with polyamines, with potential anticancer action, as well as their capacity to bind and stabilize the G-quadruplex sequence. In fact, polyamines have the potential to participate in electrostatic interactions between their positively ionized amines and the polyanionic sugar-phosphate backbone of DNA, promoting the intended bioactivities. Thereby, in this work, the chemical synthesis consisted, firstly, in the acylation of lithocholic or deoxycholic acid with succinic anhydride, followed by the coupling of polyamines using DCC as a reaction activator of this transformation. Then, the compounds were evaluated for their antiproliferative action through the MTT assay in LNCaP, MCF-7, T47D, NHDF and U87 cell lines and flow cytometry (in MCF-7 cells). The binding to and stabilization capacity of the ligand was evaluated by circular dichroism with a G-quadruplex telomeric sequence. The results of this work show that deoxycholic acid analogues, with emphasis on product 7, which seems to have cytotoxicity and selective effect on hormone-dependent tumours. However, this action is not correlated with its telomeric G-quadruplex stabilization, since it has poor stabilizing effect of this sequence, with a tendency to stabilize the parallel topology. The flow cytometry studies reveal the hypothesis that this compound might promote apoptosis in MCF-7 cells. In conclusion, it was possible to synthetize new compounds and, one of which, product 7, appears to have some potential to continue being studied and may have an interest in creating new improved analogues, with pharmacologic potential as anticancer agents.
Cancer is a disease with high morbidity and mortality, and with a severe socio-economic impact. Despite the enormous scientific advances, the drugs currently used in the treatment of malignant tumors have low efficacy and severe side effects, so this have stimulated research in the development of new drugs in this area over the past decades. Bile acids have been widely applied in synthetic chemistry mainly due to their enantiomeric purity, high stability of the steroid nucleus, reactivity of the side chain groups, low cost and ready availability. A relevant strategy consists in development of molecules that combine its core base with polyamines, with potential anticancer action, as well as their capacity to bind and stabilize the G-quadruplex sequence. In fact, polyamines have the potential to participate in electrostatic interactions between their positively ionized amines and the polyanionic sugar-phosphate backbone of DNA, promoting the intended bioactivities. Thereby, in this work, the chemical synthesis consisted, firstly, in the acylation of lithocholic or deoxycholic acid with succinic anhydride, followed by the coupling of polyamines using DCC as a reaction activator of this transformation. Then, the compounds were evaluated for their antiproliferative action through the MTT assay in LNCaP, MCF-7, T47D, NHDF and U87 cell lines and flow cytometry (in MCF-7 cells). The binding to and stabilization capacity of the ligand was evaluated by circular dichroism with a G-quadruplex telomeric sequence. The results of this work show that deoxycholic acid analogues, with emphasis on product 7, which seems to have cytotoxicity and selective effect on hormone-dependent tumours. However, this action is not correlated with its telomeric G-quadruplex stabilization, since it has poor stabilizing effect of this sequence, with a tendency to stabilize the parallel topology. The flow cytometry studies reveal the hypothesis that this compound might promote apoptosis in MCF-7 cells. In conclusion, it was possible to synthetize new compounds and, one of which, product 7, appears to have some potential to continue being studied and may have an interest in creating new improved analogues, with pharmacologic potential as anticancer agents.
Description
Keywords
Ácido Desoxicólico Ácido Litocólico Agentes Antitumorais Esteroides G-Quadruplex