Flavonoids and Lignans fromVirola surinamensisTwigs and theirin vitroActivity againstTrypanosoma cruzi

Lopes, Norberto Peporine; Chicaro, Patrícia; Kato, Massuo Jorge; Albuquerque, Sérgio de; Yoshida, Massayoshi

doi:10.1055/s-2006-957548

Cited by 90 publications

(60 citation statements)

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“…Lopes et al (1998) showed that the tetrahydrofuran lignans veraguensin 3 and grandisin 4 (Fig. 2) were active in vitro at 5 µg/ml against the trypomastigote of T. cruzi present in murine blood, causing 100% of parasite lysis without damaging erythrocytes.…”

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confidence: 99%

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Oliveira

Vaz

Alves

et al. 2006

Mem. Inst. Oswaldo Cruz

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The natural lignans veraguensin and grandisin have been reported to be active against Trypanosoma cruzi bloodstream forms. Aiming at the total synthesis of these and related compounds, we prepared three 2-arylfurans and eight 2,5-diarylfurans. They were evaluated for their potential as T. cruzi trypanothione reductase (TR) 60% at 20 µg/ml (59 and 90 µM, respectively). On the other hand, none of the compounds was significantly active against the parasite bloodstream forms even at 250 µg/ml (0.6-1.5 mM).Key words: tropical diseases -Chagas disease -arylfurans -trypanothione reductase Chagas disease, caused by the flagellate protozoan Trypanosoma cruzi, affects 18 million people in Latin America and is responsible for 13,000 deaths every year (WHO 2002). The treatment relies on only two available drugs, nifurtimox and benznidazole, which are relatively efficient in the acute phase of the disease, but almost ineffective in the chronic phase. Nowadays, one of the most important mechanisms of Chagas disease transmission in many countries is by blood transfusion (Schmuñis 1991). In highly endemic areas it is strongly recommended the use of chemoprophylatic measures such as the addition of gentian violet to clear trypomastigotes from blood banked for transfusion (Moraes-Souza et al. 1995). Although effective, this triphenylmethane dye is not well accepted because of undesirable effects such as coloring the skin and possible mutagenicity (Wendel 1993). Thus, new drugs to treat or prevent Chagas disease are still needed.Trypanosoma cruzi enzymes such as the trypanothione reductase (TR) represent a potential drug targets because they play an essential role in the life of this parasite. TR and its substrate trypanothione, the disulfide of a glutathione-spermidine conjugate [N 1 , N 8 -bis(glutathionyl)spermidine, T(SH) 2 ] 1, help to protect the parasite from oxidative stress by maintaining an intracellular reducing environment in a manner analogous to glutathione reductase (GR) and glutathione [L-γ-glutamyl-Lcysteiylglycine, GSH] 2 (Fig. 1a) in mammalian cells (Schmidt & Krauth-Siegel 2002). TR catalyses the NADPHdependent reduction of trypanothione disulfide TS 2 to its dithiol form, T(SH) 2 . Trypanothione may be oxidized back to TS 2 (Fig. 1b) following reaction with potentially damaging radicals and oxidants generated by aerobic metabolism. Another aspect that makes TR an even more attractive target is its structural differences from the human counterpart GR. GR has a narrow positively charged active site, to accommodate the glycine carboxylates of its substrate glutathione, whereas TR has a wider, noncharged, and more hydrophobic active site (Bond et al. 1999). These differences allowed the discovery of several promising selective inhibitors of TR (Schmidt & KrauthSiegel 2002).Lignans is a class of natural products that possess important biological properties (Jensen et al. 1993). Lopes et al. (1998) showed that the tetrahydrofuran lignans veraguensin 3 and grandisin 4 (Fig. 2) were active in vitro at 5 µg/ml aga...

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confidence: 99%

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Oliveira

Vaz

Alves

et al. 2006

Mem. Inst. Oswaldo Cruz

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“…Nearly all relevant spectral details of the isolated metabolites were closely comparable to the corresponding 13 C and 1 H features of grandisin, 4,33 but no data for the second aromatic ring were observed by the integration of signals. In addition, a hemiacetal proton was observed at d 4.71 (d, 1H), attached to a carbon at d 111.1 as observed in the HMQC experiment.…”

Section: Resultsmentioning

confidence: 59%

“…1 In particular, the optically active tetrahydrofuran lignans display a wide range of pharmacological activities, including anti-parasite, [2][3][4] antibacterial, 5 antifungal, 6 antitumoral, 7 anti-inflammatory 8,9 and platelet-activating factor (PAF) inhibition. [10][11][12] Several non-symmetrical 2,5-diaryltetrahydrofuran lignans, shown in Table 1, have been isolated from Piper species (Piperaceae) containing either piperonyl, veratryl or 3,4,5-trimethoxyphenyl substituent at 2 and 5 positions and methyl groups at 3 and 4 positions attached to the tetrahydrofuran ring, as illustrated by (+)-calopiptin (1, P. schmidtii), 5-[rel-(2S,3S,4S,5S)-5'-(3'',4''-dimethoxyphenyl)-3',4'-dimethyl-2'-tetrahydro-furanyl)]-1,3-benzodioxole (2, P. wightii), (2S,3R,4S,5R)-3,4-dimethyl-2,5-bis(3',4'-dimethoxyphenyl)-tetrahydrofuran (3, P. clarkii), (±)-galgravin (4, P. futokadsura, P. hancei, P. puberculum, P.wallichii), (-)-galbelgin (5, P. attenuatum, P. futokadsura, P. thomsoni, P. wightii), (+)-grandisin (6, P. polysyphorum), (+)-machilin G (7, P. schmidtii, P. wightii), (+)-veraguensin (8, P. cuneifolium, P. futokadsura, P. puberculum) and (-)-zuonin A (9, P. schmidtii).…”

Section: Introductionmentioning

confidence: 99%

“…13 Other bis-tetrahydrofuran lignans have also been described from Achillea lingulata (Asteraceae). 14 In previous reports, Martins et al 3 described the isolation of (-)-grandisin (6) from Piper solmsianum and Lopes and co-workers 4,15 from Virola surinamensis (Rol.) Warb, which belong to Piperaceae and Myristicaceae, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…The tetrahydrofuran lignan (-)-grandisin (6) showed a potent trypanocidal activity against the trypomastigote form of Trypanosoma cruzi, responsible for Chagas´s disease in Latin America, at 5 µg mL -1 leading to a total parasite lysis after 24 h, without hematiae damage. 4 Furthermore, veraguensin (8) also isolated from Virola surinamensis 4 preserved this anti-parasite pattern along with a potent platelet-activating factor (PAF) inhibitory activity that may be involved in the mechanisms of the parasite growing and differentiation. 16 Nevertheless, attempts to overcome the poor water solubility of compounds 6 and 8 for in vivo evaluation, comprising semi-synthetic modifications such as O-demethylation of the methoxy groups attached to the aromatic rings, led to byproducts due to the presence of two benzylic carbons in the tetrahydrofuran ring that were very unstable under acidic or base conditions.…”

Section: Introductionmentioning

confidence: 99%

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Biotransformation of a tetrahydrofuran lignan by the endophytic fungus Phomopsis Sp.

Verza¹,

Arakawa²,

Lopes³

et al. 2009

J. Braz. Chem. Soc.

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A biotransformação da lignana tetraidrofurânica, (-)-grandisina, pelo fungo endofítico Phomopsis sp, obtido de Viguiera arenaria, conduziu à formação de um novo metabólito caracterizado como 3,4-dimetil-2-(4'-hidróxi-3',5'-dimetóxifenil)-5-metóxi-tetraidrofurano. O metabólito foi analisado contra o parasita Trypanosoma cruzi, o agente causador da doença de Chagas, e mostrou uma atividade tripanocida (IC 50 9,8 µmol L -1 ) similar ao precursor natural (IC 50 3,7 µmol L -1 ).The biotrasformation of the tetrahydrofuran lignan, (-)-grandisin, by the endophitic fungus Phomopsis sp, obtained from Viguiera arenaria, led to the formation of a new compound determined as 3,4-dimethyl-2-(4'-hydroxy-3',5'-dimethoxyphenyl)-5-methoxy-tetrahydrofuran. The metabolite was evaluated against the parasite Trypanosoma cruzi, the causative agent of Chagas's disease, and showed a trypanocidal activity (IC 50 9.8 µmol L -1 ) similar to the natural precursor (IC 50 3.7 µmol L -1 ).Keywords: biotransformation, 2,5-diaryltetrahydrofuran, endophytic fungus, (-)-grandisin, trypanocidal activity IntroductionThe lignan family is a large group of natural products with noteworthy therapeutic activity as illustrated by podophyllotoxin derivatives (e. g. etoposide) with antitumoral activity. 1 In particular, the optically active tetrahydrofuran lignans display a wide range of pharmacological activities, including anti-parasite, 2-4 antibacterial, 5 antifungal, 6 antitumoral, 7 anti-inflammatory 8,9 and platelet-activating factor (PAF) inhibition. [10][11][12] Several non-symmetrical 2,5-diaryltetrahydrofuran lignans, shown in Table 1, have been isolated from Piper species (Piperaceae) containing either piperonyl, veratryl or 3,4,5-trimethoxyphenyl substituent at 2 and 5 positions and methyl groups at 3 and 4 positions attached to the tetrahydrofuran ring, as illustrated by (+)-calopiptin P. futokadsura, P. hancei, P. puberculum, P.wallichii), (-)-galbelgin (5, P. attenuatum, P. futokadsura, P. thomsoni, P. wightii), (+)-grandisin (6, P. polysyphorum), (+)-machilin G (7, P. schmidtii, P. wightii), (+)-veraguensin (8, P. cuneifolium, P. futokadsura, P. puberculum) and (-)-zuonin A (9, P. schmidtii). 13 Other bis-tetrahydrofuran lignans have also been described from Achillea lingulata (Asteraceae). 14 In previous reports, Martins et al. 3 described the isolation of (-)-grandisin (6) from Piper solmsianum and Lopes and co-workers 4,15 from Virola surinamensis (Rol.) Warb, which belong to Piperaceae and Myristicaceae, respectively. The tetrahydrofuran lignan (-)-grandisin (6) showed a potent trypanocidal activity against the trypomastigote form of Trypanosoma cruzi, responsible for Chagas´s disease in Latin America, at 5 µg mL -1 leading to a total parasite lysis after 24 h, without hematiae damage. 4 Furthermore, veraguensin (8) also isolated from Virola surinamensis 4 preserved this anti-parasite pattern along with a potent platelet-activating factor (PAF) inhibitory activity that may be involved in the mechanisms of the parasite growing and diffe...

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In vitro metabolism of the lignan (−)‐grandisin, an anticancer drug candidate, by human liver microsomes

Barth

Habenschus

Moreira

et al. 2015

Drug Testing and Analysis

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(-)-grandisin is a tetrahydrofuran lignan that displays important biological properties, such as trypanocidal, anti-inflammatory, cytotoxic, and antitumor activities, suggesting its utility as a potential drug candidate. One important step in drug development is metabolic characterization and metabolite identification. To perform a biotransformation study of (-)-grandisin and to determine its kinetic properties in humans, a high performance liquid chromatography (HPLC) method was developed and validated. After HPLC method validation, the kinetic properties of (-)-grandisin were determined. (-)-grandisin metabolism obeyed Michaelis-Menten kinetics. The maximal reaction rate (Vmax ) was 3.96 ± 0.18 µmol/mg protein/h, and the Michaelis-Menten constant (Km ) was 8.23 ± 0.99 μM. In addition, the structures of the metabolites derived from (-)-grandisin were characterized via gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analysis. Four metabolites, 4-O-demethylgrandisin, 3-O-demethylgrandisin, 4,4'-di-O-demethylgrandisin, and a metabolite that may correspond to either 3,4-di-O-demethylgrandisin or 3,5-di-O-demethylgrandisin, were detected. CYP2C9 isoform was the main responsible for the formation of the metabolites. These metabolites have not been previously described, demonstrating the necessity of assessing (-)-grandisin metabolism using human-derived materials.

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Flavonoids and Lignans fromVirola surinamensisTwigs and theirin vitroActivity againstTrypanosoma cruzi

Cited by 90 publications

References 1 publication

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Arylfurans as potential Trypanosoma cruzi trypanothione reductase inhibitors

Biotransformation of a tetrahydrofuran lignan by the endophytic fungus Phomopsis Sp.

In vitro metabolism of the lignan (−)‐grandisin, an anticancer drug candidate, by human liver microsomes

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