Biomimetic in vitro oxidation of lapachol: A model to predict and analyse the in vivo phase I metabolism of bioactive compounds

Niehues, Michael; Barros, Valéria P.; Emery, Flávio da Silva; Dias‐Baruffi, Marcelo; Assis, Marilda das Dores; Lopes, Norberto Peporine

doi:10.1016/j.ejmech.2012.06.042

Cited by 39 publications

(30 citation statements)

References 33 publications

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“…Several in vitro biomimetic models were developed for phase I metabolism investigations. 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].…”

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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“…Examples of this property can be found in literature, where it was able to react with drugs (Leod et al, 2007;Mac Leod et al, 2008) and natural products (De Santis Ferreira et al, 2012;Niehues et al, 2012;Rocha et al, 2014) to confirm or predict metabolism products. Therefore, the biomimetic system using Jacobsen catalyst and H 2 O 2 was successfully applied to obtainment of the non-aromatic oxidation products of GQ-11 in order to bring more evidence for the proposed metabolite structures.…”

Section: Discussionmentioning

confidence: 99%

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

et al. 2018

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Number of references: 55Number of words in the Abstract: 241 Number of words in the Introduction: 750Number of words in the Discussion: 828Nonstandard abbreviations: ADME, absorption, distribution, metabolism, and excretion; CL h , hepatic clearance; CL int , intrinsic clearance; ESI, electrospray ionization; GQ-11, 5-(indol-3-ylmethylene)-3-(4-methylbenzyl)-thiazolidine-2,4-dione; HLM, human liver microsome; LC-HRMS, liquid chromatography coupled to high resolution mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MRM, multiple reaction monitoring; PPARγ, peroxisome proliferatoractivated receptor gamma; RLM, rat liver microsome; t 1/2 , half-life; TZD, thiazolidinedione;This article has not been copyedited and formatted. The final version may differ from this version. AbstractThiazolidinediones are drugs used to treat type 2 diabetes mellitus; however, there remain several safety concerns regarding the available drugs in this class. Therefore, the search for new thiazolidinedione candidates is still ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, which is one of the most commonly used thiazolidinediones, and GQ-11, a new N-substituted thiazolidinedione, were investigated in terms of their metabolic activity in rat and human liver microsomes, in order to assess their metabolic stability and to investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the metabolite investigation was performed using Ultra-Performance Liquid Chromatography (UPLC) coupled to a hybrid quadrupole-time of flight (Q-Tof) mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 mL/kg/min for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 mL/kg/min for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product, which may be related to the mechanism of ring opening, and the toxicity of pioglitazone. The metabolites of GQ-11 are products of oxidation; no ring opening metabolite was observed for GQ-11. In conclusion, in the same experimental conditions, a ring opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to ring opening is probably related to N-substitution in the thiazolidinedione ring.

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“…In the presence of oxygen donors, Jacobsen catalyst (Figure 1) is known to mimic various reactions of CYP450 enzymes, such as oxidation and oxygenation. Some recent examples in the literature include studies on drugs such as primidone [15], carbamazepine [16], and other synthetic drugs [14], as well as other active natural products such as lapachol [17] and grandisin [18]. …”

Section: Introductionmentioning

confidence: 99%

Jacobsen Catalyst as a Cytochrome P450 Biomimetic Model for the Metabolism of Monensin A

Rocha

Oliveira

Pazin

et al. 2014

BioMed Research International

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Monensin A is a commercially important natural product isolated from Streptomyces cinnamonensins that is primarily employed to treat coccidiosis. Monensin A selectively complexes and transports sodium cations across lipid membranes and displays a variety of biological properties. In this study, we evaluated the Jacobsen catalyst as a cytochrome P450 biomimetic model to investigate the oxidation of monensin A. Mass spectrometry analysis of the products from these model systems revealed the formation of two products: 3-O-demethyl monensin A and 12-hydroxy monensin A, which are the same ones found in in vivo models. Monensin A and products obtained in biomimetic model were tested in a mitochondrial toxicity model assessment and an antimicrobial bioassay against Staphylococcus aureus, S. aureus methicillin-resistant, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli. Our results demonstrated the toxicological effects of monensin A in isolated rat liver mitochondria but not its products, showing that the metabolism of monensin A is a detoxification metabolism. In addition, the antimicrobial bioassay showed that monensin A and its products possessed activity against Gram-positive microorganisms but not for Gram-negative microorganisms. The results revealed the potential of application of this biomimetic chemical model in the synthesis of drug metabolites, providing metabolites for biological tests and other purposes.

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Biomimetic in vitro oxidation of lapachol: A model to predict and analyse the in vivo phase I metabolism of bioactive compounds

Cited by 39 publications

References 33 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

New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N-Substituted Thiazolidinedione

Jacobsen Catalyst as a Cytochrome P450 Biomimetic Model for the Metabolism of Monensin A

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