O-Demethylation reaction

Berman MH, AC Frazer (1992) Importance of tetrahydrofolate and ATP in the anaerobic O-demethylation reaction for phenylmethylethers. Appl Environ Microbiol 58 925-931. 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

Table II summarizes the results together with the detailed experimental conditions. As is evident, metabolic activities were detectable in these 3 aquatic species, but the rate was far lower as compared with mammalian hepatic enzume preparations, and the oxidative activities in snail were particularly low although the possibility was not ruled out of the presence of inhibitors of mixed-function oxidases in the fractions. The O-demethylation reaction proceeds extremely slowly in the enzyme preparation of aquatic animals, at less than one hundredth that of mammals.

Meunier G, Meunier B (1985) Peroxidase-catalyzed O-demethylation reactions. Quinone imine formation from 9-methoxyellipticine derivatives. J Biol Chem 260 10576-10582... 

The results for the hydrolysis of chlorobenzene, o-chlorotoluene and p-chloroanisole in presence of cuprous oxide at different temperatures (Fig. 14) show a good selectivity for the reaction of the chlorobenzene. But, the p-chloroanisole is also transformed by a secondary demethylation reaction into the corresponding p-chlorophenolate. 

These transformation reactions are similar in part to those previously observed for laudanosine (201) and for the aporphine-benzylisoquinoline alkaloid thalicarpine (202). Laudanosine underwent regiospecific O-demethylation at... 

Biotransformations of morphinan alkaloids have been reported for plant, fungal, and mammalian enzymatic systems with emphasis on rather specific reactions such as the reduction of ketones, N- and O-demethylation, and perox-idative transformations. Furuya et al. used immobilized tissue culture cells of Papaver somniferum to accomplish the selective reduction of codeinone (135) to codeine (136) (207) (Scheme 30). Suspension cultures of a well-established cell line of P. somniferum were grown for one week as a source of cell mass for immobilization in calcium alginate. The cells continued to live in the alginate matrix for 6 months maintaining their biological activity. The reduction of co-... 

Fig. 9.15. Metabolism of acephate (9.82) in mammals [156]. Pathway a leads to toxification by producing methamidophos. Pathways b-d are reactions of detoxification that lead to an O-demethyl, a demethylthio, and a deacetylamino metabolite, respectively.

All evidence presented here indicates that the methoxime-to-ketone reaction is enzymatic, but the nature of the reaction is unclear. Hydrolysis by an uncharacterized hydrolase, as postulated by the authors, is a valid assumption. However, one should not dismiss another possibility, namely oxidative O-demethylation to the oxime, followed by spontaneous oxime-to-ketone hydrolysis, and stereospecific reduction, as explained above. 

The difluoroboronate chelate complexes of the derivatives of tellur-achromones 104 (X = O) and tellurathiochromone 104 (X = S), which may be viewed as the corresponding tellurachromylium zwitterions 105, were prepared through the demethylation reaction of the 5-methoxy derivatives 104 under the action of the complex BF3-Et20 (88MI4). 

The mechanism in hepatic cellular metabolism involves an electron transport system that functions for many drugs and chemical substances. These reactions include O-demethylation, N-demethyla-tion, hydroxylation, nitro reduction and other classical biotransformations. The electron transport system contains the heme protein, cytochrome P-450 that is reduced by NADPH via a flavoprotein, cytochrome P-450 reductase. For oxidative metabolic reactions, cytochrome P-450, in its reduced state (Fe 2), incorporates one atom of oxygen into the drug substrate and another into water. Many metabolic reductive reactions also utilize this system. In addition, there is a lipid component, phosphatidylcholine, which is associated with the electron transport and is an obligatory requirement for... 

Dayer P, Leemann T, Stribemi R. Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 dbl activity. Clin Pharmacol Ther 1989 45 34-40. 

Zimmermann T, Schlenk R, Pfaff P, et al. Prediction of phenotype for dextromethorphan O-demethylation by using polymerase chain reaction in healthy volunteers. Arzneimittelforschung 1995 45 41 13. 

Sodium benzylselenolate in refluxing DMF is a superior reagent for O-demethylation at the hindered 1-, 8-, and 11-positions of the aporphine nucleus. Methylenedioxy-functions survive the reaction.47 The microbial transformation of glaucine produces mainly norglaucine and predicentrine (25).48... 

Another type of transformation catalyzed by peroxidases and occurring through a radical mechanism is the demethylation of heteroatoms, such as -OMe and -NMe groups [40-42], Figure 6.2d shows, as an example, the HRP-catalyzed O-demethylation of 9-methoxyellipticine [41]. This reaction occurs through the elimination of methanol in very mild conditions. It should be noted that... 

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