Quinone imine formation

Meunier G, Meunier B (1985) Peroxidase-catalyzed O-demethylation reactions. Quinone imine formation from 9-methoxyellipticine derivatives. J Biol Chem 260 10576-10582... 

SCHEME 4 Quinone-imine formation with amodiaquine and acetaminophen. 

In some cases, quinone-imine formation requires an initial hydroxylation step as illustrated with the nonsteroidal anti-inflammatory drug and idiosyncratic hepatotoxin diclofenac. Thus, CYP-catalyzed aromatic hydroxylation para to the aniline nitrogen affords thepara-hydroxydiclofenac isomers, which can then undergo CYP or peroxidase-mediated oxidation to the quinone-imines amenable to trapping with GSH (Scheme 6) (Tang et al., 1999 Miyamoto et al., 1997). The aniline nitrogen in quinone-imine derivatives can also be part of a heterocyclic... 

Besides participating in quinone-imine formation, primary anilines can also undergo an alternate CYP- or peroxidase-catalyzed bioactivation pathway that involves an initial Y-hydroxylation on the aniline nitrogen to afford the Y-hydroxylamine metabolite followed by further oxidation to a reactive nitroso species, which, in some cases, can be trapped with GSH (Scheme 10)... 

The formation of the nitroxyl radical and quinone imine precludes the possibility of the recovery of amine and, hence, any of the above reactions interrupts the cycle at the aminyl radical. Taking these reactions into account, we come to the following expression for the coefficient / ... 

Another drug with a high incidence of hepatotoxicity is the acetylcholinesterase inhibitor tacrine. Binding of reactive metabolites to liver tissue correlated with the formation of a 7-hydroxy metabolite [13], highly suggestive of a quinone imine metabolite as the reactive species. Such a metabolite would be formed by further oxidation of 7-hydroxy tacrine (Figure 8.11). 

Researchers have found that the substitution of two methyl groups on the benzene ring in the acetaminophen molecule results in the formation of an analog that is essentially resistant to the metabolic reactions that result in the formation of N-acetyl-p-henzo-quinone imine and, hence, prevent toxic reactions involved with the use of acetaminophen. Researchers believe that the presence of the methyl groups interferes with enzyme actions that, in the first step of the reaction by which N-acetyl-p-benzo-quinone imine is produced, convert hydrogen atoms on the benzene rings in acetaminophen to hydroxyl groups. 

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

Autoxidation of 9-hydroxyellypticine (60) is a good example of degradation of phenols, showing the formation of a quinone-imine (XV) and an oxidative dimer (XVI, Fig. 12). Phenols can be quite stable in the protonated... 

Many xenobiotics, including a wide variety of quinones and nitro compounds, will accept an electron from almost any redox flavoenzyme. The microsomal reduction of nitroaromatic compounds, quinones, quinone-imines, some azoaromatic compounds, paraquat, and tetrazolium salts is catalyzed by NADPH-cytochrome P-450 reductase [44], One-electron transfer to these electron acceptors has been proved to be obligatory in the case of quinone and nitro compounds, and is probably obligatory in other cases as well. Therefore, a reduction of an aromatic compound by NADPH-cytochrome P-450 reductase can probably be assumed to form a free radical metabolite. In contrast, free radical formation by reductive dehalogenation is totally cytochrome P-450-dependent, with the reductase being inactive. 

To rationalize the remarkable regioselectivity and stereoselectivity of these alkylation reactions, Potier and co-workers (777,775) proposed that a stacking interaction occurs between quinone imine 256 and the nucleic acid base prior to covalent bond formation. Moreover, the appropriate intermolecular NOE is observed to support this contention. The fact that these ribonucleotide adducts form so easily may suggest that ellipticine quinone imines could alkylate at the 3 end of transfer RNA or at similar sites on other RNA molecules to inhibit protein synthesis. Thus, RNA would seem to be a reasonable target for elliptinium and related ellipticines (775). 

An explanation of these results and determination of the mechanism(s) of inhibition by the isocoumarins required a complex series of kinetic analyses and X-ray crystallographic studies [186]. These studies showed that the mechanistic pathway (see Figure 2.8) was pH-dependent [187] and that different forms of the inhibited enzymes, illustrated by (8a), (8c) and (8d), could be isolated. Ring-opening results in formation of an intermediate acyl-enzyme (8a), which, in some cases, can be isolated but which can also eliminate chloride to produce a reactive quinone imine methide (8b). This reactive intermediate is either trapped by solute or solvent, to produce a second acyl-enzyme (8c) [188] or alkylated by His-57 to produce an irreversibly inactivated enzyme (8d) [189]. The ratio between (8c) and (8d) has been shown to vary widely. 

Formation of the quinone imine dye is measured continually every 5 seconds between the 150th and 240th second at 530 nm by the reflectometer. The activity can be calculated via the data obtained from a 2-point calibration. 

SCHEME 17. Electrochemical formation of a quinone imine ketal... 

Imine formation. An example of this route is Echavarren and Stille s use of a simple intramolecular imine formation between a quinone moiety and an amino group to complete the nucleus (Scheme 25) of amphi-medine 105 (88JA4051). The quinone 159 was prepared by a palladium-catalyzed cross-coupling of 5,8-dimethoxyquinolin-4-yl triflate 157 (from... 

The nitroxide 56 traps in its mesomeric form 56c radicals ROO . Quinone imine iV-oxide 62, is formed via alkylperoxycyclohexadieneimine intermediate. 62 is destroyed by the further attack of ROO . Benzoquinone (63) and nitroso- (64, n = l) and nitrobenzene (64, n=2) are formed in the ultimate phase of the lifetime of 62 [65]. An alternative pathway for oxidation of 56 with ROO in cumene autoxidation suggests formation of an olefin and hydroxylamine 66 as CB antioxidant species [66] ... 

Route a is similar to biosynthesis shown in Scheme 1, and many total syntheses have been described using this route. Route a is divided into three methods (Scheme 3) 1) first formation of the quinone moiety followed by imine formation, 2) first formation of the cyclic amine followed by oxidation, and 3) the direct iminoquinone formation of the substrates having an azide side chain developed by us (see Schemes 24 and 27). 

Oxidation of the neurotoxin 6-aminodopamine 102 at concentrations higher than 5 x 10 M leads to formation of the tetrahydrophenoxazine derivative 104 (38%) (92X8515). A mechanism involving intermediate formation of the quinone imine 103 followed by 6-exo-trig cyclisation has been proposed (Scheme 27). 

Three variations of this methodology lead to different heterocyclic products. Use of the mono-oxime 115 results in formation of the benzoxazole 116 after elimination of methanol (equation (14)) (89T4585). Use of two moles of ]V-phenyliminophosphorane (PhN - PPhs) gives the 2,3-dihydro-l,2,3-benzoxadiazole 117 (40%) (equation (15)), presumably after initial formation of the quinone imine (02SC2779). Reaction with phosphanylidene phosphoranes (ArP - PMes) gives 1 2-benzodioxophospholanes 118 (equation (16)) (04CC146). 

However, in a pharmacokinetic study in 10 healthy subjects of both slow and fast acetylator status, isoniazid 300 mg daily for 7 days modestly decreased the total clearance of a single 500-mg dose of paracetamol by 15%. Moreover, the clearance of paracetamol to oxidative metabolites was decreased Similarly, in a further study in 10 healthy slow acetylators of isoniazid, the formation of paracetamol thioether metabolites and oxidative metabolites was reduced by 63% and 49%, respectively, by isoniazid 300 mg daily. However, one day after stopping isoniazid, the formation of thioether metabolites was increased by 56%, and this returned to pretreatment values 3 days after the discontinuation of isoniazid. In yet another study in 10 healthy subjects taking isoniazid prophylaxis, the formation clearance of paracetamol to A -acetyl-p-benzo-quinone imine (NAPQI) was inhibited by 56% when the paracetamol was given simultaneously with the daily isoniazid dose, but when the paracetamol was taken 12 hours after the isoniazid, there was no difference in NAPQI formation clearance, compared with the control phase (1 to 2 weeks after isoniazid had been discontinued). However, when the results were analysed by acetylator status, it appeared that the NAPQI formation clearance was increased in fast acetylators taking paracetamol 12 hours after the isoniazid dose. ... 

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