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

Rocha, Bruno Alves; Oliveira, Anderson Rodrigo Moraes de; Pazin, Murilo; Dorta, Daniel Junqueira; Rodrigues, Andresa Piacezzi Nascimento; Berretta, Andresa Aparecida; Peti, Ana Paula Ferranti; Moraes, Luiz Alberto Beraldo de; Lopes, Norberto Peporine; Pospı́šil, Stanislav; Gates, Paul J.; Assis, Marilda das Dores

doi:10.1155/2014/152102

Cited by 9 publications

(9 citation statements)

References 39 publications

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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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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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“…The oxidants and catalysts were dissolved in ACN:H 2 O (9:1 v/v) for the reactions, except for PhIO which was dissolved in ACN. All combinations of oxidant, substrate and catalyst were evaluated in catalyst:oxidant:substrate ratios of 1:10:10, 1:20:20 and 1:30:30 (0.1 mM catalyst:1 mM oxidant:1 mM substrate, 0.1 mM catalyst:2 mM oxidant:2 mM substrate and 0.1 mM catalyst:3 mM oxidant:3 mM substrate) . The control reactions involved the absence of a catalyst.…”

Section: Methodsmentioning

confidence: 99%

“…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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“…Metabolism data in chicken showed that parent lasalocid is excreted at about 10% the administered dose with a great number of minor metabolites (each less than 5% the whole [ 14 C] activity) of greater polarity that would likely correspond to mono‐ and multihydroxylated lasalocid (see Section 3.2.2.1). Hydroxylated metabolites of the ionophore antibiotics monensin sodium, salinomycin and narasin have been shown to exert reduced ionophoric activity and therefore much lesser toxicity than the parent compound (Donoho, ; Dimenna et al., ; Rocha et al., ; EFSA FEEDAP Panel, ). It can be reasonably assumed that the same would occur with lasalocid hydroxy‐metabolites.…”

Section: Assessmentmentioning

confidence: 99%

Safety and efficacy of Avatec® 150G (lasalocid A sodium) for chickens for fattening and chickens reared for laying, and modification of the terms of authorisation for chickens for fattening, chickens reared for laying, turkeys for fattening, minor avian species (pheasants, guinea fowl, quails and partridges) except laying birds

Rychen¹,

Aquilina²,

Azimonti³

et al. 2017

EFS2

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Avatec® 150G is an anticoccidial feed additive containing 15% of the active ingredient lasalocid A sodium, an ionophore anticoccidial. The tolerance study indicated that oral administration of lasalocid A sodium via feed at doses at and above the targeted lasalocid dose of 125 mg/kg was not tolerated in chickens for fattening. Consequently, no safe dose can be established by the tolerance study submitted. Concurrent administration of lasalocid with tiamulin and certain other medicinal substances should be avoided. Lasalocid sodium has a selective antimicrobial activity against Gram-positive bacterial species while many Enterobacteriaceae are naturally resistant. Induction of resistance and/or cross-resistance was not observed in experimental conditions. Lasalocid A sodium is not genotoxic and not carcinogenic. The newly conducted cardiovascular study in dogs indicated an acute no-observed-adverse-effect level (NOAEL) of 1 mg/kg body weight (bw) per day. Since this NOAEL is above the lowest NOAEL of 0.5 mg/kg bw per day previously identified in a 2-year toxicity study in rats and a developmental study in rabbits, it is concluded that this NOAEL (0.5 mg/kg bw per day) is an appropriate base for establishing an Acceptable Daily Intake of 0.005 mg lasalocid sodium/kg bw. The use of lasalocid A sodium from Avatec ® 150G at the highest proposed level of 125 mg/kg complete feed is safe for the consumer. For compliance with the maximum residue limits (MRLs), a withdrawal period of 3 days is necessary. No risk for the user is expected from the use of Avatec ® 150G. The use of lasalocid A sodium from Avatec ® 150G in feed for chickens for fattening and chickens reared for laying up to the highest proposed dose does not pose a risk for the environment. Insufficient evidence of the anticoccidial efficacy of lasalocid A sodium was provided in chickens for fattening/reared for laying. This is an open access article under the terms of the Creative Commons Attribution-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited and no modifications or adaptations are made.The EFSA Journal is a publication of the European Food Safety Authority, an agency of the European Union. SummaryFollowing a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Avatec ® 150G (lasalocid A sodium) for chickens for fattening and chickens reared for laying. The FEEDAP Panel was also requested to assess the compliance with maximum residue limits (MRLs) established by Implementing Regulation (EU) No 1277/2014 for chickens for fattening, chickens reared for laying, turkeys for fattening and other minor avian species, except laying birds. In addition, the proposed reduction of the withdrawal period (from five to two days) is evaluated. Avatec ® 150G is an anticoccidial feed additive containing 15% of the active ingredient lasalocid A sodium, an ionophore a...

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

Cited by 9 publications

References 39 publications

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

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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