Alcaloides indólicos revertem a multirresistência em células cancerígenas

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Alcaloides indólicos revertem a multirresistência em células cancerígenas

Terça, 21.03.2017

A multirresistência (MDR) é considerada o principal obstáculo no tratamento do cancro. É um fenómeno multifatorial que pode envolver vários mecanismos, nomeadamente um aumento do efluxo do fármaco, devido à sobre expressão de proteínas transportadoras da família ABC. O principal transportador ABC envolvido na MDR é a glicoproteína-P (P-gp/ABCB1), que atua como uma bomba de efluxo transportando os fármacos anticancerígenos para fora das células. Um dos principais interesses do grupo de Química de Produtos Naturais do Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, é obter compostos de origem natural capazes de modular a atividade transportadora da glicoproteína-P em células cancerígenas multirresistentes. Em colaboração com o “Department of Medical Microbiology and Immunobiology, University of Szeged”, Hungria, e o Centro de Estudos Moçambicanos e de Etnociências (CEMEC), Universidade Pedagógica, Maputo, este grupo de investigação desenvolveu um conjunto de inibidores da atividade transportadora da glicoproteína-P por derivatização molecular de dois alcaloides indólicos, isolados da planta medicinal Africana Tabernaemontana elegans. Os resultados obtidos são promissores e poderão contribuir para o desenvolvimento de inibidores eficazes das proteínas transportadoras ABC, considerado uma estratégia importante para superar a MDR.


Angela Paterna1, Annamária Kincses2, Gabriella Spengler2, Silva Mulhovo3, Joseph Molnár2, Maria-José U. Ferreira1*

1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal

2 Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary

3 Centro de Estudos Moçambicanos e de Etnociências (CEMEC), Faculty of Natural Sciences and Mathematics, Pedagogical University, 21402161 Maputo, Mozambique


Dregamine (1) and tabernaemontanine (2), two epimeric monoterpene indole alkaloids isolated in large amount from the roots of the African plant Tabernaemontana elegans, were derivatized, yielding ten imine derivatives, as previously described (3-12). In the present study, aiming at increasing the pool of analogues for establishing structure-activity relationships (SAR), compounds 1 and 2 were further submitted to several chemical transformations, yielding thirteen new derivatives (13-25). Their structures were assigned by spectroscopic methods, including 1D and 2D NMR experiments. Compounds 1-25 were evaluated for their effects on the reversion of multidrug resistance (MDR) in cancer cells mediated by P-glycoprotein (P-gp/ABCB1), through combination of functional and chemosensitivity assays, using a human ABCB1-transfected mouse T-lymphoma cell model. SAR analysis showed that different substituents at C-3 and at the indole nitrogen led to different ABCB1 modulatory effects. When compared to the parent compounds, a remarkable enhancement in MDR reversal activity was found for derivatives sharing a new aromatic moiety. Thus, the strongest ability as MDR reversers, and a manifold activity when compared to verapamil, was found for compound 8, the epimeric compounds 9 and 10, and compound 15, bearing pyrazine, 5-bromo-pyridine, and 4-methoxybenzyl moieties, respectively. In drug combination assays, all compounds tested were revealed to interact synergistically with doxorubicin. Collectively, the results indicate that some of these derivatives may be promising leads for overcoming MDR in cancer.

European Journal of Medicinal Chemistry

http://dx.doi.org/10.1016/j.ejmech.2017.01.044