Drug metabolism alkene

Not unexpectedly, cycloalkene oxides are equally important as alkene oxides in medicinal chemistry and drug metabolism, as illustrated below with a few selected examples. Other compounds of interest that will not be discussed here include epoxytetrahydrocannabinols and endogenous 16,17-ep-oxy steroids. 

Figure 9.18 Relative contribution of CYP3A4-catalyzed double bond epoxidation to drug metabolism. For carbamazepine, this represents the major metabolic route, while for tamoxifen CYP3A4-catalyzed epoxidation of the alkene is negligible and the enzyme instead Y-demethylates it.

Some drugs fall within the class of functionalized alkenes discussed here. Thus, the anti-inflammatory agent alclophenac (10.63) contains an O-allyl group. Its epoxide 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) [141]. 

Oxidation Athene Epoxidation. Alkenes may react to produce epoxides (alternatively, sometimes, the alkenes do not react and are metabolically stable). The epoxide is unstable and is subject to ring opening via a nucleophilic attack. The anticonvulsant drug carbamazepine is metabolized via epoxidation to yield carbamazepine-10,11-epoxide in turn, this is rapidly opened to yield carbamazepine-10,ll-diol. 

Alkenes. Alkenes are, in general, metaholically stable. The majority of alkene-containing drugs do not exhibit significant rapid metabolism at the double bond. There are some isolated examples of alkene-containing compounds that undergo epoxidation, catalyzed by mixed-function oxidase, or that add water across the double bond to give an alcohol. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

Turn to Appendix A and pick five different drugs to demonstrate the following phase I metabolic processes oxidation (dealkylation, arene/alkene, heteroatom), reduction, and... 

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