Estudo fitoquímico de Aristolochia cordigera e síntese de lignanas com potencial antimalárico
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2017-02-15
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Universidade Estadual Paulista (Unesp)
Resumo
Este trabalho descreve um estudo comparativo da variabilidade química intraespecífica de espécies de Aristolochia cordigera, coletadas em duas regiões diferentes do Brasil, Bioma Cerrado (semiárido) e Bioma Amazônia (litoral). A utilização de CG-EM e métodos estatísticos levaram a identificação de 56 compostos. Altas concentrações de palmitona e germacreno-D nos extratos hexânicos de folhas das plantas destes respectivos biomas, caracterizam a procedência da planta. Os estudos fitoquímicos dos extratos levaram ao isolamento e identificação de 19 compostos conhecidos, incluindo lignanas, neolignanas, ácidos aristolóquicos, indol-β-carbolina e alcaloides indólicos. Além disso, dois novos alcaloides indólicos, 3,4-dihidro-hirtiosulawesina e 6-O-(β-glucopiranosil)hirtiosulawesina foram isolados e cis-eupomatenoide-7, uma nova neolignana, foi obtida em mistura com o seu isômero conhecido eupomatenoide-7. Suas estruturas foram determinadas por métodos espectroscópicos, principalmente por RMN 1D e 2D e HRESIMS, sendo que a ocorrência de alcaloides indólicos está sendo descrita pela primeira vez na família Aristolochiaceae. Também foram avaliadas a susceptibilidade in vitro de formas amastigotas intracelulares e formas promastigotas de Leishmania amazonensis dos alcaloides e do eupomatenoide-7. Esta neolignana apresentou baixa atividade contra formas promastigotas (IC50 de 46 μM) e toxicidade contra formas amastigotas em concentrações de 50 e 100 μM, enquanto que os alcaloides não apresentaram atividade inibitória nas mesmas condições experimentais. Varios dos alcaloides isolados também foram avaliados in vitro contra Plasmodium falciparum. O alcaloide 6-O-(β-glucopiranosil)hirtiosulawesina exibiu atividade, com um valor de IC50 de 5 μM e um índice de selectividade (IS) superior a 50. A lignana 8-epi-aristoligona e 35 análogos desta, com diferentes substituintes nos anéis A e C foram obtidos por síntese. A lignana também foi transformada em ariltetralóis e ariltetralenos. A atividade antiplasmodial destes derivados foi avaliada. Os derivados mais ativos foram 4'-bromo-4,5-dimetoxi-2,7'-ciclolignan-7-ona e 3',4'-dimetoxi-4,5-dimetil-2,7'-ciclolignan-7-ona, com IC50 = 1,3 ± 0,8 μM e IC50 = 2,6 ± 0,8 μM, respectivamente. Assim, a avaliação da atividade inibitória in vitro contra L. amazonensis e P. falciparum sugere que os compostos isolados de A. cordigera assim como os derivados sintéticos obtidos podem ser investigados como novos “scaffolds” moleculares para o desenvolvimento de fármacos antiparasitários.
This work describes a comparative study on the intraspecific chemical variability of Aristolochia cordigera species, collected in two different regions of Brazil, Biome Cerrado (semi-arid) and Biome Amazônia (coastal). The used of GC-MS and statistical methods led to identification of 56 compounds. Higher concentrations of palmitone and germacrene-D in the hexanes extracts of the leaves of plants from these respective biomes characterized the plant provenance. Moreover, phytochemical studies on the extracts led to the isolation and identification of 19 known compounds, including lignans, neolignans, aristolochic acids, indole-β-carboline and indole alkaloids. In addition, two new indole alkaloids, 3,4-dihydro-hyrtiosulawesine and 6-O-(β-glucopyranosyl)hyrtiosulawesine were isolated and cis-eupomatenoid-7, a new neolignan, was obtained in a mixture with its known isomer eupomatenoid-7. Their structures were determined by spectroscopic methods, mainly by 1D- and 2D-NMR and HRESIMS. The occurrence of indole alkaloids is being described for the first time in the Aristolochiaceae family. Moreover, the in vitro susceptibility of intracellular amastigotes and promastigotes forms of Leishmania amazonensis to the alkaloids and eupomatenoid-7 was evaluated. This neolignan exhibited low activity against promastigotes (IC50 = 46 µM) and toxicity against amastigotes at concentrations of 50 and 100 µM, while the alkaloids did not show inhibitory activity at the same experimental conditions. Several of the isolated alkaloids were also evaluated in vitro against Plasmodium falciparum. The alkaloid 6-O-(β-glucopyranosyl)hyrtiosulawesine exhibited activity, with IC50 value of 5 µM and selectivity index (SI) higher than 50. The lignan 8’-epi-aristoligone and its 36 analogous, with different substituents on the A and C rings, were obtained by synthesis. The lignan was also transformed into aryltetralols and aryltetralenes. The antiplasmodial activity of these derivatives were evaluated. The most active derivatives were 4’-bromo-4,5-dimethoxy-2,7’-cyclolignan-7-one and 3’,4’-dimethoxy-4,5-dimethyl-2,7’-cyclolignan-7-one, with IC50 = 1.3 ±0.8 µM and IC50 = 2.6 ±0.8 µM, respectively. Thus, the in vitro inhibitory activity evaluation against L. amazonensis and P. falciparum suggests that the isolated compounds from A. cordigera as well as the synthetic derivatives obtained may be investigated as novel molecular scaffolds for antiparasitic drug development.
This work describes a comparative study on the intraspecific chemical variability of Aristolochia cordigera species, collected in two different regions of Brazil, Biome Cerrado (semi-arid) and Biome Amazônia (coastal). The used of GC-MS and statistical methods led to identification of 56 compounds. Higher concentrations of palmitone and germacrene-D in the hexanes extracts of the leaves of plants from these respective biomes characterized the plant provenance. Moreover, phytochemical studies on the extracts led to the isolation and identification of 19 known compounds, including lignans, neolignans, aristolochic acids, indole-β-carboline and indole alkaloids. In addition, two new indole alkaloids, 3,4-dihydro-hyrtiosulawesine and 6-O-(β-glucopyranosyl)hyrtiosulawesine were isolated and cis-eupomatenoid-7, a new neolignan, was obtained in a mixture with its known isomer eupomatenoid-7. Their structures were determined by spectroscopic methods, mainly by 1D- and 2D-NMR and HRESIMS. The occurrence of indole alkaloids is being described for the first time in the Aristolochiaceae family. Moreover, the in vitro susceptibility of intracellular amastigotes and promastigotes forms of Leishmania amazonensis to the alkaloids and eupomatenoid-7 was evaluated. This neolignan exhibited low activity against promastigotes (IC50 = 46 µM) and toxicity against amastigotes at concentrations of 50 and 100 µM, while the alkaloids did not show inhibitory activity at the same experimental conditions. Several of the isolated alkaloids were also evaluated in vitro against Plasmodium falciparum. The alkaloid 6-O-(β-glucopyranosyl)hyrtiosulawesine exhibited activity, with IC50 value of 5 µM and selectivity index (SI) higher than 50. The lignan 8’-epi-aristoligone and its 36 analogous, with different substituents on the A and C rings, were obtained by synthesis. The lignan was also transformed into aryltetralols and aryltetralenes. The antiplasmodial activity of these derivatives were evaluated. The most active derivatives were 4’-bromo-4,5-dimethoxy-2,7’-cyclolignan-7-one and 3’,4’-dimethoxy-4,5-dimethyl-2,7’-cyclolignan-7-one, with IC50 = 1.3 ±0.8 µM and IC50 = 2.6 ±0.8 µM, respectively. Thus, the in vitro inhibitory activity evaluation against L. amazonensis and P. falciparum suggests that the isolated compounds from A. cordigera as well as the synthetic derivatives obtained may be investigated as novel molecular scaffolds for antiparasitic drug development.
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Aristolochia cordigera, Aristolochiaceae, Lignoides, Alcaloides indólicos, Síntese de lignanas, Antiplasmodial, Antileishmanial