Demethylation s. Dealkylation

Dealkylation 0-, N-, and S-Dealkylation. Probably the best known example of O-dealkylation is the demethylation of p-nitroanisole. Due to the ease with which the product, /t-nilrophcnol, can be measured, it is a frequently used substrate for the demonstration of CYP activity. The reaction likely proceeds through formation of an unstable methylol intermediate (Figure 7.5). 

When X = 0 or S in reaction 4 (Fig. 13.3), the metabolic reactions are known as 0-deal-kylations or S-dealkylations, respectively. O-demethylation is a typical case of the former reaction. And when X = halogen in reactions... 

Aliphatic and aromatic methyl thioethers undergo S-dealkylation to thiols and carbonyl compounds. For example, 6-methylthiopurine is demethylated to give the active anticancer drug 6-mercaptopurine (Fig. 10.14). Other thioethers are oxidized to sulfoxides (see N- and S-oxidations). 

Reactions involving sulfur-linked substituents have been exclusively dealkylations of S-alkyl substituents to yield a thiocarbonyl group. Debenzyl-ations under mild conditions with aluminum chloride in benzene were mentioned earlier (Section IV,A,2,a). Pyridine demethylates salts 137 selectively to give 175. ° ... 

Dealkylation usually occurs on O- or A -alkyl group.s in CMs. The reaction may involve an unstable oxidized intermediate and the alkyl group is detached and becomes an aldehyde (Kulkami and Hodgson, 1980). O- and A -dealkylations are illustrated in Fig. 8. In JV.Ai-dimethyl-carbatnates, one of the W-methyl groups can undeigo //-demethylation after hydroxylation. Af-demethylation... 

Decomposition of this unstable intermediate produces an amine plus either an aldehyde or a ketone. The term used to describe this process depends on which of the two cleavage products one is interested in. If most of the original molecule remains with the amine (e.g. the N-demethylation of olanzapine shown in Figure 9.21), it s considered oxidative N-dealkylation, but if it ends up in the carbonyl-containing fragment (e.g. conversion of a primary phenethy-lamine to a phenylacetaldehyde and ammonia) it would be instead referred to as oxidative deamination. Notably, FMOs can also carry out N-oxidations of secondary and tertiary amines, for example the pyrrolidine nitrogen of nicotine, but not a-hydroxylations to produce the cleavage products that CYPs can provide. ... 

Metoprolol is another beta-blocker that is predominantly eliminated by hepatic metabolism [38]. In humans, metoprolol is eliminated by several oxidation pathways, including benzylic hydroxylation (a-hydroxylation), which results in an active metabolite and accounts for 10% of the dose [39]. This pathway is stereoselective for S(—)-metoprolol. The major metabolic pathway, however, is O-demethylation and further oxidation to a carboxylic acid metabolite that accounts for 65% of the dose [38]. O-demethylation favors R(- -)-metoprolol [39] and facilitates the stereoselectivity observed in the plasma concentrations of metoprolol. A third metabolic pathway (N-dealkylation) accounts for < 10% of the dose in humans [39]. 

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