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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
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8.2 Epoxides 103
Fig. 8.4 Schematic showing relative softness and hardness of nucleophiles and elec-trophiles as an indicator of sites of reaction of electrophilic metabolites.
• Sulfhydryl of cysteine or glutathione
• Sulfur of methionine
Primary or secondary amino of lysine, arginine or histidine
Amino groups of purine basesin RNA and DNA Oygen of purines and pyrimidines in DNA and
• a,p-unsaturated carbonyl compounds, quinones and quinone imines.
• Epoxides, alkyl sulphates and halides
• Aryl carbonium and nitreniun ions
• Benzylic carbonium ions
• Alkyl carbonium ions
the reactive metabolites. This system is saturable, so that a threshold dose, or other factors leading to glutathione depletion, is needed to trigger toxicity.
Fig. 8.5 Schematic showing the generation of a reactive metabolite, its reaction with a protein target, and toxicity resulting from a direct mechanism (protein essential to cell function) or one involving the immune system.
Covalent binding to liver proteins
Direct hepatotoxicity Hepatotoxicity of the immunoallergenic type
Epoxide metabolites can be generated from a variety of aromatic systems. Anticonvulsants are a class of drug whose side-effects, such as hepatic necrosis and aplastic anaemia, are thought to be mediated by chemically reactive epoxide metabolites formed by cytochrome P450 oxidation. For instance phenytoin (Figure 8.6) toxicity is correlated with oxidation and the inhibition of epoxide hydrolase [8].
Carbamazepine exerts its anticonvulsant activity through its own action on voltage sensitive sodium channels and those of its relatively stable 10-11-epoxide. The compound shows a number of potential toxicities including skin rash, hepatic necrosis and teratogenicity. It is possible the 10-11-epoxide is the causative agent, but struc-
104 8 Toxicity
Fig. 8.6 Structure of pheny-toin, a drug believed to assert its toxicity through reactive epoxide metabolites.
tural studies [9] suggest other epoxide metabolites of the aromatic ring may be responsible in part. Oxcarbazepine (Figure 8.7) is a related drug that cannot form the 10-11-epoxide and owes part of its activity to its hydroxyl metabolite. Oxcarbazepine is much less teratogenic in animal models and shows a lower preponderance of skin rash [8,10].
Fig.8.7 Structures of carbamezepine (A), its 10-11-epoxide metabolite (B), and oxcarbazepine (C) and its hydroxyl metabolite (D).
Quinone Imines
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].
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
8.3 Quinone Imines 105
Fig. 8.8 Oxidation of phenacetin to a benzoquinone intermediate.
^ P450
the case of acetaminophen [11] (Figure 8.9), suggesting that such structural features in a molecule should be avoided.
Such reactions can occur in other molecules containing aromatic amine functions without a para oxygen substituent. For instance diclofenac can be oxidized to a minor metabolite (5-OH) diclofenac which can be further oxidized [12] to the benzoqui-nine imine metabolite (Figure 8.10). Again, the reactivity of this intermediate has been implicated in the hepatotoxicity of the compound.
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).
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 (DMBI) forms an imi-noquinone [14]. Formation of the iminoquinone from DMBI is catalysed by
Fig. 8.9 Structures of amodiaquine and its quinone imine metabolite.
106 8 Toxicity
Fig. 8.11 Metabolism of tacrine to hydroxyl metabolites, the 5-hydroxy derivative of which can be further oxidized to the reactive quinone imine.
myeloperoxidase (the major oxidizing enzyme in neutrophils) and HOCl (the major oxidant produced by activated neutrophils). The pathway for formation of the imino-quinone is illustrated in Figure 8.12.
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