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Compostos com atividade antitumoral da planta africana Momordica balsamina L.: moduladores da glicoproteína-P
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A multirresistência farmacológica (MDR) tem sido apontada como um dos principais motivos para a ineficácia da quimioterapia no tratamento do cancro. Um dos fatores responsáveis pelo desenvolvimento de MDR é a sobre-expressão da glicoproteína-P (P-gp) nas células tumorais, levando ao aumento do efluxo do fármaco do interior para o exterior da célula.
Em estudos anteriores, os triterpenos do tipo cucurbitano demonstraram uma forte atividade como moduladores da P-gp em células tumorais multirresistentes. Neste sentido, este trabalho teve como principal objetivo a obtenção de uma pequena biblioteca de compostos ativos, resultantes do estudo fitoquímico do extrato metanólico das partes aéreas da planta Africana Momordica balsamina L. (Cucurbitaceae).
Do fracionamento do extrato metanólico, por processos cromatográficos, resultaram cinco compostos novos, com o esqueleto do cucurbitano, denominados balsacurbitriol (2.1), balsacurbepoxitol (2.2), ácido balsacurbitóico (2.3), balsacurbital (2.4) e balsacurbinol (2.5), e cinco compostos já descritos anteriormente com o mesmo esqueleto: karavilagenina C (1.92), karavilagenina A (2.6), karavilagenina B (2.7), kuguacina B (2.8) e kuguacina C (2.9) e o esteroide, 24-etil-5α-colesta-7,22,25-trien-3-ol (2.10). A oxidação da karavilagenina C (1.92) e do esteroide (2.10) originou os compostos 2.11 e 2.12, respetivamente. A atribuição das estruturas químicas dos compostos foi realizada através da análise dos seus dados físicos e espectroscópicos, que incluíram: infravermelho, espectrometria de massa e estudos de RMN unidimensionais (1H, 13C, DEPT) e bidimensionais (HMQC, HMBC, COSY e NOESY).
Os compostos (1.92 e 2.1-2.12) foram avaliados quanto ao seu efeito citotóxico e como moduladores da P-gp em células T L5178Y de linfoma de rato, transfetadas com o gene humano ABCB1, e em células do adenocarcinoma do colón humano multirresistentes, através do ensaio de acumulação da rodamina 123. A maioria dos compostos mostrou uma forte atividade moduladora da P-gp (FAR > 10) e uma interação sinérgica com o fármaco antitumoral doxorrubicina, o que corroborou o seu potencial como reversores de MDR.
Multidrug resistance (MDR) is considered one of the main reasons of cancer chemotherapy failure. One of the most significant mechanisms of MDR is due to the overexpression of P-glycoprotein (P-gp) that acts as an extrusion pump for chemotherapeutic agents, thus decreasing their intracellular concentration. In previous studies, cucurbitane-type triterpenes were found to be strong P-gp modulators in multidrug resistant tumour cells. In this way, this dissertation aimed at generating a small library of compounds through the phytochemical study of the African medicinal plant Momordica balsamina L. (Cucurbitaceae). Fractionation of the methanol extract of Momordica balsamina aerial parts, by chromatographic techniques, such as extensive column chromatography, preparative thin layer chromatography and high-performance liquid chromatography (HPLC), afforded five new compounds with the cucurbitane skeleton, named balsacurbitriol (2.1), balsacurbepoxitol (2.2), balsacurbitoic acid (2.3), balsacurbital (2.4) and balsacurbinol (2.5), along with five known compounds with the same skeleton: karavilagenin C (1.92), karavilagenin A (2.6), karavilagenin B (2.7), kuaguacin B (2.8) and kuguacin C (2.9), and a steroid, 24-ethyl-5α-cholesta-7,22,25-trien-3-ol (2.10). Oxidation of karavilagenin C (1.92) and the steroid (2.10) yielded the derivatives 2.11 and 2.12, respectively. The chemical structures of the compounds were deduced from their physical and spectroscopic data, which included infrared spectroscopy, mass spectrometry and extensive one-dimensional (1H, 13C, DEPT) and two-dimensional (HMQC, HMBC, COSY e NOESY) NMR experiments. Compounds 1.92 and 2.1-2.12 were assessed for their cytotoxic activities and as P-gp modulators in human ABCB1-gene transfected L5178Y mouse lymphoma cells and resistant human colon adenocarcinoma cells by the rhodamine-123 accumulation assay. Most of the compounds showed strong P-gp modulating activity (FAR > 10) and a synergistic interaction with the antitumor drug doxorubicin, confirming their potential as MDR reversers.
Multidrug resistance (MDR) is considered one of the main reasons of cancer chemotherapy failure. One of the most significant mechanisms of MDR is due to the overexpression of P-glycoprotein (P-gp) that acts as an extrusion pump for chemotherapeutic agents, thus decreasing their intracellular concentration. In previous studies, cucurbitane-type triterpenes were found to be strong P-gp modulators in multidrug resistant tumour cells. In this way, this dissertation aimed at generating a small library of compounds through the phytochemical study of the African medicinal plant Momordica balsamina L. (Cucurbitaceae). Fractionation of the methanol extract of Momordica balsamina aerial parts, by chromatographic techniques, such as extensive column chromatography, preparative thin layer chromatography and high-performance liquid chromatography (HPLC), afforded five new compounds with the cucurbitane skeleton, named balsacurbitriol (2.1), balsacurbepoxitol (2.2), balsacurbitoic acid (2.3), balsacurbital (2.4) and balsacurbinol (2.5), along with five known compounds with the same skeleton: karavilagenin C (1.92), karavilagenin A (2.6), karavilagenin B (2.7), kuaguacin B (2.8) and kuguacin C (2.9), and a steroid, 24-ethyl-5α-cholesta-7,22,25-trien-3-ol (2.10). Oxidation of karavilagenin C (1.92) and the steroid (2.10) yielded the derivatives 2.11 and 2.12, respectively. The chemical structures of the compounds were deduced from their physical and spectroscopic data, which included infrared spectroscopy, mass spectrometry and extensive one-dimensional (1H, 13C, DEPT) and two-dimensional (HMQC, HMBC, COSY e NOESY) NMR experiments. Compounds 1.92 and 2.1-2.12 were assessed for their cytotoxic activities and as P-gp modulators in human ABCB1-gene transfected L5178Y mouse lymphoma cells and resistant human colon adenocarcinoma cells by the rhodamine-123 accumulation assay. Most of the compounds showed strong P-gp modulating activity (FAR > 10) and a synergistic interaction with the antitumor drug doxorubicin, confirming their potential as MDR reversers.
Descrição
Tese de mestrado, Química Farmacêutica e Terapêutica, Universidade de Lisboa, Faculdade de Farmácia, 2017
Palavras-chave
Momordica balsamina Triterpenos Cucurbitano Multiresistência farmacológica Glicoproteína-P Teses de mestrado - 2017