Occurrence of the NIH Shift upon the Cytochrome P450-Catalyzed in Vivo and in Vitro Aromatic Ring Hydroxylation of Fluorobenzenes

Koerts, J.; Soffers, A.E.M.F.; Vervoort, Jacques; Jäger, Alfred; Rietjens, Ivonne M. C. M.

doi:10.1021/tx980053i

Cited by 52 publications

(49 citation statements)

References 39 publications

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“…1). Such mechanisms were reported in higher organisms and bacteria for halogenated as well as alkyl substituents (9,10,12,15,22). Incubations of Burkholderia cepacia with 3,5-dimethyl-4-hydroxybenzaldehyde, syringaldehyde, or 5-bromovanillin led to the formation of para hydroxylation of the phenol with a simultaneous shift of the aldehyde group to the vicinal position (15).…”

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confidence: 63%

Degradation of a Nonylphenol Single Isomer by Sphingomonas sp. Strain TTNP3 Leads to a Hydroxylation-Induced Migration Product

Corvini

Meesters

Schäffer

et al. 2004

Appl Environ Microbiol

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Sphingomonas sp. strain TTNP3 degrades 4(3,5-dimethyl-3-heptyl)-phenol and unidentified metabolites that were described previously. The chromatographic analyses of the synthesized reference compound and the metabolites led to their identification as 2(3,5-dimethyl-3-heptyl)-1,4-benzenediol. This finding indicates that the nonylphenol metabolism of this bacterium involves unconventional degradation pathways where an NIH shift mechanism occurs.Nonylphenol (NP) is a ubiquitous pollutant which mainly results from the biodegradation of widely used NP polyethoxylate surfactants, and it is well known for its endocrine systemdisrupting potential (5,8,11,13,20,21). NP is used as part of a technical mixture which consists of more than 20 branched isomers of the nonyl chain (23, 28). Although some studies report an easy degradation of the NP with a linear alkyl chain (4-n-NP) through oxidation of the side chain, the situation is different for branched isomers of NP (2,25,26). The main reason for the poor degradability of NP is a quaternary carbon atom (␣-carbon) of the branched alkyl chain, which is involved in the attachment of the nonyl group to the phenol moiety. More than 85% of the isomers of the technical mixture contain such quaternary ␣-carbon atoms (26, 28). Some strains belonging to the genera Sphingomonas, Sphingobium, and Pseudomonas have been reported to be able to degrade the branched isomers of NP, but the catabolic pathways in these bacteria remain poorly characterized (6,7,18,19,21,24).Previously, it was proven that the dead-end product of the degradation of 4(3Ј,5Ј-dimethyl-3Ј-heptyl)-phenol (p353NP) diastereomers is 3,5-dimethyl-3-heptanol (nonanol). This metabolite corresponds to the nonyl chain of p353NP, where the aromatic ring has been replaced by a hydroxyl group (3). It remains to be elucidated how the very stable quaternary C atom structure of NP can lead to the formation of nonanol. Nonanol has been found only in cultures of Sphingomonas sp. strain TTNP3 and Sphingomonas cloacae, so these bacteria seem to possess particular degradation pathways for NP (3,6,21). Recently, it was reported that neither 4-n-NP nor shortchain alkylphenols were degraded by Sphingomonas sp. strain TTNP3, whereas the diastereomers of the branched single isomer p353NP (Fig. 1) led to the formation of ring-oxidized metabolites (4). Ring-oxidized metabolites were detected only in the intracellular fraction and were shown to be different from 4(3Ј,5Ј-dimethyl-3Ј-heptyl)-catechol (Fig. 1b) and 4(3Ј,5Ј-dimethyl-3Ј-heptyl)-resorcinol (Fig. 1c), hydroxylated at positions C-2 and C-3 (Fig. 1), respectively. We hypothesize the formation of metabolites which undergo either hydroxylation with an alkyl chain internal rearrangement, as is the case for bisphenol A (14), or hydroxylation-induced migration of the alkyl chain immediately after hydroxylation at position C-4. The latter process would lead to the formation of 2(3Ј,5Ј-dimethyl-3Ј-heptyl)-1,4-benzenediol (o353NHQ) (Fig. 1d). In order to identify definitively these metabolites ...

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confidence: 63%

Degradation of a Nonylphenol Single Isomer by Sphingomonas sp. Strain TTNP3 Leads to a Hydroxylation-Induced Migration Product

Corvini

Meesters

Schäffer

et al. 2004

Appl Environ Microbiol

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“…The in vitro data from liver microsomes showed greater formation of the NIH shifted fluoroaromatic products which demonstrates that this process can be important for fluorinated analogues [25]. This shift can therefore result in cases where the introduction of fluorine into a compound does not prevent oxidation at that site.…”

Section: Removal Of Fluorine To Develop Celecoxibmentioning

confidence: 94%

The role of fluorine in medicinal chemistry

Shah

Westwell

2007

Journal of Enzyme Inhibition and Medicinal Chemistry

636

392

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The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18 F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.

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“…The mechanism presumably proceeds via an epoxidation of TCC by P450 TCC or 3Ј,4Ј-epoxy TCC, followed by a dechlorination to 3,4-dichloro 4Ј-hydroxycarbanilide, as discussed by Ariyoshi et al (1997) for the metabolism of polychlorinated biphenyl 153. By a rearrangement (the so-called NIH shift) of the epoxide intermediate and subsequent dechlorination, 3,4-dichloro-3Ј-hydroxycarbanilide could also be formed as described for the oxidative metabolism of similar chlorinated compounds (Ariyoshi et al, 1997;Koerts et al, 1998). However, based on the fragment ions provided in Table 1, the exact position of the hydroxyl group remains unknown.…”

Section: Electrochemical Studies Of Tcc Show Reactive Metabolitesmentioning

confidence: 99%

Electrochemistry-Mass Spectrometry Unveils the Formation of Reactive Triclocarban Metabolites

Baumann¹,

Lohmann²,

Rose³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Triclocarban (3,4,4-trichlorocarbanilide, TCC) is a widely used antibacterial agent in personal care products and is frequently detected as an environmental pollutant in waste waters and surface waters. In this study, we report novel reactive metabolites potentially formed during biotransformation of TCC. The oxidative metabolism of TCC has been predicted using an electrochemical cell coupled online to liquid chromatography and electrospray ionization mass spectrometry. The electrochemical oxidation unveils the fact that hydroxylated metabolites of TCC may form reactive quinone imines. Moreover, a so-far unknown dechlorinated and hydroxylated TCC metabolite has been identified. The results were confirmed by in vitro studies with human and rat liver microsomes. The reactivity of the newly discovered quinone imines was demonstrated by their covalent binding to glutathione and macromolecules, using ␤-lactoglobulin A as a model protein. The results regarding the capability of the electrochemical cell to mimic the oxidative metabolism of TCC are discussed. Moreover, the occurrence of reactive metabolites is compared with findings from earlier in vivo studies and their relevance in vivo is argued.

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Occurrence of the NIH Shift upon the Cytochrome P450-Catalyzed in Vivo and in Vitro Aromatic Ring Hydroxylation of Fluorobenzenes

Cited by 52 publications

References 39 publications

Degradation of a Nonylphenol Single Isomer by Sphingomonas sp. Strain TTNP3 Leads to a Hydroxylation-Induced Migration Product

Degradation of a Nonylphenol Single Isomer by Sphingomonas sp. Strain TTNP3 Leads to a Hydroxylation-Induced Migration Product

The role of fluorine in medicinal chemistry

Electrochemistry-Mass Spectrometry Unveils the Formation of Reactive Triclocarban Metabolites

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