In vitro metabolism study of the promising anticancer agent the lignan (−)-grandisin

Messiano, Gisele B.; Santos, Renan Augusto da Silva; Ferreira, Leandro de Santis; Simões, Rodrigo Almeida; Jabor, Valquíria Aparecida Polisel; Kato, Massuo Jorge; Lopes, Norberto Peporine; Pupo, Mônica Tallarico; Oliveira, Anderson Rodrigo Moraes de

doi:10.1016/j.jpba.2012.08.028

Cited by 23 publications

(18 citation statements)

References 24 publications

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“…Our group recently applied Jacobsen catalyst ([Mn (salen)]) to produce similar metabolites of CYP450 enzymes yielding the product in good scale [21,22]. Comparative analysis confirmed the presence of the same putative metabolite in biomimetic oxidative model, microsomal fractions and in vivo experiments, reinforcing the importance of this methodology for pre-clinical trials [20,23,24]. In this context, the aim of this work was to investigate the metabolism of erythraline in the pig cecum model and through biomimetic reactions, in order to improve information on its pre-clinical pharmacokinetic and also on the biological activity of the putative metabolite.…”

Section: Introductionmentioning

confidence: 99%

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

Guaratini

Silva

Bizaro

et al. 2014

BMC Complement Altern Med

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BackgroundErythrina verna, popularly known as “mulungu”, is a Brazilian medicinal plant used to treat anxiety. Erythrina alkaloids have been described in several species of Erythrina, which have biological and therapeutic properties well known that include anxiolytic and sedative effects.MethodsIn this work, in vitro metabolism of erythraline (1), the major spirocyclic alkaloid of Erythrina verna, was studied in the pig cecum model and by biomimetic phase I reactions. The biomimetic reactions were performed with Jacobsen catalyst to produce oxidative metabolites and one metabolite was isolated and evaluated against cancer cells, as HL-60 (promyelocytic leukemia), SF-295 (Glioblastoma) and OVCAR-8 (ovarian carcinoma).ResultsErythraline exhibited no metabolization by the pig microbiota and a main putative metabolite was formed in a biomimetic model using Jacobsen catalyst. This metabolite was isolated and identified as 8-oxo-erythraline (2). Finally, erythraline and the putative metabolite were tested in MTT model and both compounds showed no important cytotoxic activity against tumor cells.ConclusionsThe alkaloid erythraline was not metabolized by intestinal microbiota, but it was possible to identify its oxidative metabolite from biomimetic reactions. So these data are interesting and stimulate other studies involving this alkaloid, since it is present in phytomedicine products and there are not reported data about the metabolism of erythrina alkaloids.

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Section: Introductionmentioning

confidence: 99%

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

Guaratini

Silva

Bizaro

et al. 2014

BMC Complement Altern Med

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“…To date, many investigations have been performed to explore (−)‐grandisin metabolism using several in vitro models, such as fungi, insects, pig ceca, Jacobsen catalysts, and rat hepatic microsomes . Considering that the liver is the major drug‐metabolizing organ, liver‐derived systems are the most suitable for metabolic studies .…”

Section: Introductionmentioning

confidence: 99%

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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“…Accuracy was defined as the percent of deviation between the true value and the measured value, and precision was expressed as relative standard deviation (RSD%) (11). The accuracy and precision of the method were determined by analyzing a set of quality control (QC).…”

Section: Methods Validationmentioning

confidence: 99%

Antitumor Activity of DMAKO-05, a Novel Shikonin Derivative, and Its Metabolism in Rat Liver Microsome

Wang

Zhou

et al. 2014

AAPS PharmSciTech

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Abstract. The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug.

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In vitro metabolism study of the promising anticancer agent the lignan (−)-grandisin

Cited by 23 publications

References 24 publications

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

In vitro metabolism studies of erythraline, the major spiroalkaloid from Erythrina verna

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

Antitumor Activity of DMAKO-05, a Novel Shikonin Derivative, and Its Metabolism in Rat Liver Microsome

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