Benzoquinone-4-imines

The chlorination of the antibacterial sulfonamide sulfamethoxazole was initiated by N-chlorination of the primary amine. Further reaction of the A,A-dichlorinated compound resulted in the final production of 3-amino-5-methyloxazole and 1,4-benzoquinone-imine (Dodd and Huang 2004). 

Bedner M, WA Maccrehan (2006) Transformation of acetaminophen by chlorination produces the toxicants 1,4-benzoquinone and iV-acetyl-/)-benzoquinone imine. Environ Sci Technol 40 516-522. 

Blair, LA., Boobis, A.R., Davies, D.J. and Cresp, T.M. (1980). Paracetamol oxidation, synthesis and reactivity of N-acetyl-/>-benzoquinone imine. Tetrahedron Lett. 21, 4947-4950. 

Coles, B., Wilson, I. and Wardman, P. (1988). The spontaneous and enzymatic reaction of N-acetyl-/>-benzoquinone imine with glutathione, a stopped flow kinetic study. Arch. Biochem. Biophys. 264, 253-260. 

Dahlin, D.C., Miwa, G.T., Lu, A.Y.H. and Nelson, S.D. (1984). N-Acetyl-p-benzoquinone imine a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl Acad. Sci. USA 81, 1327-1331. 

Moore, M., Thor, H., Moore, G., Nelson, S., Moldeus, P. and Orrenius, S. (1985). The toxicity of acetaminophen and N-acetyl-/>-benzoquinone imine in isolated hcpatocytes is associated with thiol depletion and increased cytsolic Ca. J. Biol. Chem. 260, 13035-13040. 

NAP Neutrophil-activating peptide NAPQI N-acetyl-p-benzoquinone imine... 

Imines 268 (Ar = phenyl, p-anisyl, p-chloro-phenyl) are dimerized on heating in aprotic solvents to give the yellow tetraphenyl p-benzoquinone imines 267 and (or) their reduction products, the colorless p-phenylene diamine derivatives 270ss ... 

Manno et al. [43] observed the formation of superoxide during the oxidation of arylamines by rat liver microsomes. Noda et al. [44] demonstrated that microsomes are able to oxidize hydrazine into a free radical. In contrast, hepatic cytochrome P-450 apparently oxidizes paracetamol (4 -hydroxyacetanilide) to A-acetyl-p-benzoquinone imine by a two-electron mechanism [45]. Younes [46] proposed that superoxide mediated the microsomal S -oxidation of thiobenzamide. 

The antibacterial agent sulfamethoxazole produced chlorinated and nonchlorinated DBFs when reacted with chlorine [91]. A ring-chlorinated product was formed via halogenation of the aniline moiety at sub-stoichiometiic concentrations of chlorine. 3-Amino-5-methylisoxazole, sulfate, and A-chloro-p-benzoquinone imine were formed via rupture of the sulfamethoxazole sulfonamide moiety at stoichiometric excess of chlorine. 

The reaction of the lipid-regulator gemfibrozil with free chlorine yielded four chlorinated derivatives of this compound [94]. Chlorination of acetaminophen (paracetamol) generated 11 discernible DBFs, including the toxic compounds 1,4-benzoquinone and A-acetyl-p-benzoquinone imine and two ring chlorination products, chloro-4-acetamidophenol and dichloro -acetamidophenol [95]. 

Fig. 8.10 Scheme showing metabolism of diclofenac by oxidation (A) to benzoquinone imine (C) metabolites. 

For the other esters 54 was not directly detectable, but its existence could be inferred from its decomposition products 60 or 61. A-acetyl-para-benzoquinone imine, 60, was detected during the hydrolysis of AlP Its decomposition products, 62 and 63, accounted for >90% of 47, and about 30% of 46c in buffers from pH 3.0 to 8.0 containing 0.5 M KCl. The identity of 60 was confirmed by the equivalence of its decomposition kinetics and reaction products (61-63) observed in solutions of 47, or its 4-ethoxy analogue, to that of authentic 60 throughout the pH range 1.0 to 8.0. It was not possible to directly detect 60 in the hydrolysis of 46c and 46d, but its characteristic decomposition products were detected. ... 

Bioactivation is a classic toxicity mechanism where the functional group or the chemical structure of the drug molecule is altered by enzymatic reactions. For example, the enzymatic breakdown of the analgesic acetaminophen (paracetamol), where the aromatic nature and the hydroxyl functionality in paracetamol are lost, yields A -acetyl-p-benzoquinone imine, a hepatotoxic agent. Paracetamol can cause liver damage and even liver failure, especially when combined with alcohol. 

Synthesis and Kinetics of Hydrolysis of 3,5-Dimethyl-N-acetyl-p-benzoquinone Imine 235... 

Figure 7.19 Proposed metabolic activation of paracetamol to a toxic, reactive intermediate /V-acetyl-p-benzoquinone imine (NAPQI). This can react with glutathione (GSH) to form a conjugate or with tissue proteins. Alternatively, NAPQI can be reduced back to paracetamol by glutathione, forming oxidized glutathione (GSSG).

A small percentage of acetaminophen is metabolized by phase I oxidation with A-hydroxylation of the amide (8.81) (Scheme 8.22). Loss of water affords A-acetyl-p-benzoquinone imine (8.82). Benzoquinones are electron-deficient and strongly electrophilic, a trait of many toxic... 

Iodylbenzene in hot nitrobenzene effected some oxidations mimicking its isoelec-tronic ozone. Among them, the most interesting was with pyrene which was converted into a mixture of three isomeric pyrenequinones this method was advantageous for the preparation of the 4,5-isomer, despite its low yield (14%) [7]. The system iodylbenzene and catalytic amounts of vanadyl acetylacetonide was used for the synthesis of some quinone-imines from phenothiazines and related heterocycles also iV-phenyl-phenylsulphonamide was converted into N-(phenylsulphonyl)-1,4-benzoquinone-imine. 

The 2-amino- and 2-acylamino-l- -aminoanthraquinones (231) are also photolabile, giving imidazoles of type 225 or acyldihydro-imidazoles (221).111 This may suggest that the photoreaction follows a different mechanism from that of the thermal process, and is more related to the reactions of benzoquinones described below. Thus, mesomeric or tautomeric forms such as 232 and 233 may be invoked to explain the photoreactions, by analogy with the corresponding benzoquinone imines described below. 

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