Quinones imines

Toxicity by metabolism is not confined to the liver since oxidative systems occur in many organs and cells. Amodiaquine is a 4-aminoquinoline antimalarial that has been associated with hepatitis and agranulocytosis. Both side-effects are probably triggered by reactive metabolites produced in the liver or in other sites of the body. For instance polymorphonuclear leucocytes can oxidize amodiaquine. It appears that amodiaquine is metabolized to a quinone imine by the same pathway as that seen in 

Indomethacin is associated, in the clinic, with a relatively high incidence of agranulocytosis. Although indomethacin itself is not oxidized to reactive metabolites, one of its metabolites, dsemethyldeschlorobenzoylindomethacin (DMBl) forms an imi-noquinone [14]. Formation of the iminoquinone from DMBl is catalysed by 

Carbutamide was the first oral anti-diabetic, and the prototype for the sul-phonamide type of agent. Carbutamide caused marked bone marrow toxicity in man, but derivatives of this, not containing the anilino function, such as tolbutamide 

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Peroxidase horseradrsh, turnips, milk activates HjOi arid a suitable substrate, e.g., aniline quinone-imine dyes, induline, mauveine, aniline-black 4-5 varies with substrate... 

Oxidation H ir Colorant. Color-forming reactions are accompHshed by primary intermediates, secondary intermediates, and oxidants. Primary intermediates include the so-called para dyes, -phenylenediamine, -toluenediamine, -aminodiphenylamine, and p- am in oph en o1, which form a quinone monoimine or diimine upon oxidation. The secondary intermediates, also known as couplers or modifiers, couple with the quinone imines to produce dyes. Secondary intermediates include y -diamines, y -aminophenols, polyhydroxyphenols, and naphthols. Some of the more important oxidation dye colors are given in Figure 1. An extensive listing is available (24,28). 

Aminosalicylic acid (5-amino-2-hydroxybenzoic acid) [89-57-6] M 153.1, m 276-280 , 283 (dec), pK 2.74 (CO2H), pK 5.84 (NH2). Cryst as needles from H2O containing a little NaHS03 to avoid aerial oxidation to the quinone-imine. The Me ester gives needles from C6H6, m 96°, and the hydrazide has m 180-182° (From H2O). [Fallab et al. Helv Chim Acta 34 26 1951, Shavel J Amer Pharm Assoc 42 402 1953.]... 

Under the influence of peroxides aromatic amines (color developer 3) react with phenols to yield quinone imines [1]. 

Aromatic amine + 1-Naphthol-----------------> Quinone imine dyestuff. 

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 / ... 

The processes of oxidation of cyclohexadiene, 1,2-substituted ethenes, and aliphatic amines are decelerated by quinones, hydroquinones, and quinone imines by a similar mechanism. The values of stoichiometric inhibition coefficients / and the rate constants k for the corresponding reactions involving peroxyl radicals (H02 and >C(0H)00 ) are presented in Table 16.3. The/coefficients in these reactions are relatively high, varying from 8 to 70. Evidently, the irreversible consumption of quinone in these systems is due to the addition of peroxyl radicals to the double bond of quinone and alkyl radicals to the carbonyl group of quinone. 

Scheme 20 Anodic conversion of p-methoxyanilide to quinone imine.

For the quinone imine cyclization of iron complexes to carbazoles the arylamine is chemoselectively oxidized to a quinone imine before the cyclodehydrogenation [99]. The basic strategy of this approach is demonstrated for the total synthesis of the 3-oxygenated tricyclic carbazole alkaloids 4-deoxycarbazomycin B, hyellazole, carazostatin, and 0-methylcarazostatin (Scheme 17). 

Phenacetin is a classical example of a quinone imine, with oxidation of the compound by cytochrome P450 leading to a benzoquinone intermediate (Figure 8.8). The benzoquinone reacts with various cytosolic proteins to trigger direct hepatotoxi-city [6]. 

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). 

Fig. 8.11 Metabolism of tacrine to hydroxyl metabolites, the 5-hydroxy derivative of which can be further oxidized to the reactive quinone imine.

Fig. 8.21 Structures of vesnarinone, and its major metabolite veratrylpiperazinamide. The pathway metabolized by activated neutrophils gives rise to two highly reactive species, an iminium ion and a quinone imine.

One example of the effect of substitution on biological potency involves the popular drug acetaminophen (Tylenol ). Acetaminophen is almost completely metabolized in the liver with the production of harmless products that are excreted through the kidneys. A small amount of the drug maybe metabolized, however, to a toxic product, N-acetyl-p-henzo-quinone imine. In cases where large quantities... 

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. 

Glutathione is also implicated in the removal of toxic metabolites from the analgesic paracetamol (USA acetaminophen). Oxidative metabolism of paracetamol produces an A-hydroxy derivative, and this readily loses water to generate a reactive and toxic quinone imine, which interacts with proteins to cause cell damage. 

A direct synthesis of cyclic quinone imine acetals has been accomplished by the treatment of substituted phenol ethers bearing an alkyl azido side chain with IBTA (Eq. 39) [96JCS(CC)1491]. The cyclization reaction proceeds smoothly in polar and low nucleophilic solvents such as CF3CH2OH and (CF3)2CH0H in the presence of 10% MeOH. 

In the presence of water, oxidation of 4-methoxyaniline gives the quinone imine. The example 54 is converted by oxidation and ring closure to the tetrahy-drocarbazole [164],... 

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