Jacobsen catalyst as a P450 biomimetic model for the oxidation of an antiepileptic drug

Leod, Tatiana C. O. Mac; Barros, Valéria P.; Faria, André Luiz de; Schiavon, Marco A.; Yoshida, Inez Valéria Pagotto; Queiroz, Maria Eugênia Costa; Assis, Marilda das Dores

doi:10.1016/j.molcata.2007.04.003

Cited by 28 publications

(9 citation statements)

References 53 publications

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“…PhIO was used as an oxygen donor because it is considered as a standard and simple oxidant which contains a single oxygen atom and is well-adapted for the selective and clean formation of metal-oxo intermediates, Mn V (O)-salen, more efficient and selective in transferring oxygen to the substrate [13–16]. When using hydroperoxides and peracids as the oxidative agent it is possible for two competing oxygen activation mechanisms to occur.…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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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Section: Resultsmentioning

confidence: 99%

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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“…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: 98%

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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“…Since its development, the Jacobsen catalyst has been used to catalyze oxidation reactions including those of non‐functionalized olefins with enantioselectivity and alcohols . In addition, the Jacobsen catalyst has been used in studies with pharmaceuticals and natural products such as carbamazepine, monesin A, lapachol and grandisin …”

Section: Introductionmentioning

confidence: 99%

Bioinspired oxidation in cytochrome P450 of isomers orientin and isoorientin using Salen complexes

Chagas

Pontes

Albino

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Orientin and isoorientin are C‐glycosidic flavonoids, considered as markers of some plant species such as Passiflora edulis var. flavicarpa Degener, and reported in the literature to have pharmacological properties. In order to evaluate and characterize the in vitro metabolism of these flavonoids, phase I biotransformation reactions were simulated using Salen complexes. Methods These flavonoids were oxidized separately in biomimetic reactions in different proportions, using one oxidant, m‐chloroperbenzoic acid or iodosylbenzene, and one catalyst, the Jacobsen catalyst or [Mn(3‐MeOSalen)Cl]. The [Mn(3‐MeOSalen)Cl] catalyst was synthesized and characterized using spectrometric techniques. The oxidation potentials of the catalysts were compared. All reactions were monitored and analyzed using ultrahigh‐performance liquid chromatography diode‐array detection (UHPLC‐DAD) and high‐performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). Results The analysis by UHPLC‐DAD and HPLC/MS/MS showed that isoorientin produces more products than orientin and that [Mn(3‐MeOSalen)Cl] produces more products than the Jacobsen catalyst. In addition, [Mn(3‐MeOSalen)Cl], which has a higher oxidation potential, formed products with the addition of one or two atoms of oxygen, while the Jacobsen catalyst formed compounds with only one added oxygen atom. The products with the addition of one oxygen atom were mainly epoxides, while those with two added oxygens formed an epoxide in the C‐ring and incorporated the other oxygen into the glycosidic moiety. Conclusions The formation of epoxides is common in biomimetic reactions and they may represent a safety risk in medicinal products due to their high reactivity. This study may serve as a basis for subsequent pharmacological and toxicological studies that investigate the presence of these compounds as phase I metabolites, and ensure the safe use of plant products containing orientin as a chemical marker.

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Jacobsen catalyst as a P450 biomimetic model for the oxidation of an antiepileptic drug

Cited by 28 publications

References 53 publications

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

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

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

Bioinspired oxidation in cytochrome P450 of isomers orientin and isoorientin using Salen complexes

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