Alkene oxide substrates

Alkene oxides are generally quite stable chemically, indicating a much reduced chemical reactivity compared to arene oxides. Under physiologically relevant conditions, they have little capacity to undergo rearrangement reactions and are resistant to uncatalyzed hydration. As a result, many alkene oxides formed as metabolites are stable enough to allow their isolation in the absence of degrading enzymes.

Some drugs contain an unconjugated alkene group undergoing CYP-catalyzed epoxidation followed by EH-catalyzed hydration. Thus, the anti-inflammatory agent alclophenac contains an O-allyl group. Its epoxide (16, Figure 9) was found as a stable metabolite in the urine of mice and humans, and so was the diol, proving the involvement of the epoxide-diol pathway in the metabolism of this drug. The epoxide proved mutagenic, but only in the absence of a rat liver S-9 suspension (which contains EH).30 A few old barbiturates also contain an allylic group in the 5-position, e.g., allobarbital (17, Figure 9; R = allyl), and secobarbital (17, Figure 9; R = 1-methylbutyl). These compounds were substrates of the epoxide-diol pathway in rats and guinea pigs. The relative importance of this metabolic route was species dependent, but was also markedly influenced by the nature of the other C5-substituent.31

Cycloalkenes are found particularly among natural products (i.e., terpenoids) and as such are of medicinal interest. Limonene (18, Figure 9) undergoes epoxidation to the C1-C2 and C8-C9 double bonds. The two epoxide groups are then hydrated by epoxide hydrolase, but at a different rate. Indeed, incubations in rat liver microsomes showed that the hydrolysis of limonene 1,2-epoxide was 70 times slower than that of the 8,9-epoxide, a result explained by steric hindrance on the basis of these and other findings.32

A number of neurotropic agents contain a conjugated alkene group incorporated in an iminostilbene (19, Figure 9; X = >NR) or dibenzosuberene (19, Figure 9; X = >CHR or >C=CHR) ring system. Examples include the anticonvulsant carbamazepine and the antidepressants protriptyline and cyclobenzaprine. As a rule, these drugs are oxidized by cytochrome P450 to the corresponding epoxide (20, Figure 9), but hydration to the dihydrodiol (21) is usually low for reasons of unfavorable positioning in the catalytic site (for a review see5).

As a result, related tricyclic drugs yield modest or very low proportions of dihydrodiols, despite the 10,11-oxides being consistently formed. For example, both the epoxide and the dihydrodiol were characterized in the urine of rats given protriptyline (19, in Figure 9; X = >CHCH2CH2CH2NHMe), whereas cyclobenzaprine (19, Figure 9; X = >C=CHCH2CH2NMe2) did not yield the dihydrodiol despite the epoxide and other oxygenated metabolites being formed in vivo and in vitro.5

Carbamazepine (19, Figure 9; X = >NCONH2) is a major antiepileptic drug whose metabolism has interested biochemists and clinical pharmacologists for many years. Well over 30 metabolites of this drug have been characterized

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