Antitumoral, antileishmanial and antimalarial activity of pentacyclic 1,4-naphthoquinone derivatives

Abstract

As pterocarpanquinonas 8a-c, previamente sintetizadas em nosso laboratório, e uma série homóloga de derivados, substâncias 9a-c preparadas neste trabalho, foram avaliadas em células de câncer de mama (MCF-7) e em cultura dos parasitas Leishmania amazonensis e Plasmodium falciparum. As substâncias 8a-c foram mais potentes que 9a-c nas células tumorais e em Leishmania amazonensis. Por outro lado, 9a-c mostraram ser as mais ativas sobre o Plasmodium falciparum. Todas as substâncias estudadas foram biosseletivas, apresentando baixa citotoxicidade para linfócitos murinos frescos e linfócitos humanos ativados pelo mitógeno fitoemoaglutinina (PHA).Pterocarpanquinones 8a-c, previously synthesized in our laboratory, and an homologous series of derivatives, compounds 9a-c prepared in this work, were evaluated on breast cancer cells (MCF-7) and on the parasites Leishmania amazonensis and Plasmodium falciparum, in culture. Compounds 8a-c were more potent than 9a-c on tumor cells and Leishmania amazonensis. On the other hand, 9a-c showed to be more active on Plasmodium falciparum. All the compounds studied were bioselective, presenting negligible cytotoxicity against fresh murine lymphocytes and human lymphocytes activated by the mitogen phytohemaglutinin (PHA).Keywords: antineoplasic, antiparasitic, pterocarpans, naphtoquinones, oxa-Heck reaction, antimalarial, leishmanicide IntroductionPhytoalexins or phytotoxins are low molecular substances produced by plants in response to microorganism attacks.1 These compounds inhibit the growth of bacteria and fungi in vivo and in vitro, and their production during an infection can induce resistance to subsequent infections. It has been shown that pterocarpans, among other group of natural products, act as phytoalexins. Phaseollidin for example (1, Figure 1), is present in higher concentration in species of Colombian beans resistant to Colletotrichum lindemuthianum fungus, the causal agent of anthrachnose disease, than in species sensitive to this fungus.1 Pterocarpans present other interesting biological properties, depending on the pattern of substitution present at the A-and D-rings (Figure 1). For example, edunol (2), isolated from Harpalyce braziliana, a plant used in the northeast of Brazil as folk medicine, shows antiofidic activity in vitro and in vivo (mices).2 Pterocarpan 3, isolated from a plant of genus Erythrina, presents anti-HIV activity in vitro 3 and crotafuran B (4), isolated from Crotalaria pallida, has antiinflamatory properties in vitro. 4 In 1995, the catechol pterocarpan 5 was isolated from Petalostemon purpureus and showed to be active on KB cells, a human epidermoid carcinoma cell line.5 This compound and four new derivatives were synthesized and their toxicities in da Silva et al. 177 Vol. 20, No. 1, 2009 leukemia cell lines, including cell lines with MDR (multi drug resistant) phenotype were evaluated. 6 Cathecol 5 and its possible metabolite in vivo, ortho-quinone 6, showed to be the most active compounds. While 5 was bioselective, 6 presented high to...

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