N-demethylations

Dacarbazine is activated by photodecomposition (chemical breakdown caused by radiant energy) and by enzymatic N-demethylation. Formation of a methyl carbonium ion results in methylation of DNA and RNA and inhibition of nucleic acid and protein synthesis. Cells in all phases of the cell cycle are susceptible to dacarbazine. The drug is not appreciably protein bound, and it does not enter the central nervous system. 

N-Methylen-bis-nor-conaniii rZu einer Losung vonO,3 g(0,92 mMol)N-Demethyl-N-cyan-conanin in 15ml THF wird unter Stickstoff 0,15 g (4 mMol) Lithiumalanat gegeben. Nach 4Stdn. bei 20°gieBt man die Losung zu 50 g Kaliumhydroxid in 100 ml Eiswasser. Die Extraktion mit Ather liefert ein einheitliches Rohprodukt Aus-beute 0,28 g (100% d. Th.) F 170° (aus Athanol). 

Nor-conanin Zu einer klarcn Losung von 0,2 g (5,3 mMol) Lithiumalanat in 10 ml THF wird unter Stickstoff 0,3 g (0,92 mMol) N-Demethyl-N-cyan-conanin in 3 ml THF gegeben. Man erhitzt 1 Stde. unter RiickfluB, kiihlt ab, versetzt mit einer Losung von 25 g Kaliumhydroxid in 50 ml Wasser und extrahiert mit Ather. Nach Abdamp-fcn des Losungsmittels erhalt man ein einheitliches farbloses Harz Ausbeute 0,28 g (100°/u d.Th.). 

Olesen, O. V. Linnet, K. (2001). Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations. /. Clin. Pharmacol., 41, 823-32. 

Liu, Z. Q., Shu, Y., Huang, S. L. et al. (2001). Effects of CYP2C19 genotype and CYP2C9 on fluoxetine N-demethylation in human liver microsomes. Acta Pharmacologica Sinica, 22 85-90. 

The use of ultraviolet irradiation to transform cocaine (98), 3a-benzoyloxytropane (14), and tropacocaine (43) to the corresponding N-demethylated products has been described 107). 

Wu et al. (156) found that photolysis of 13-substituted dihydroprotober-berine metho salts 296 in methanol similarly afforded the corresponding spirobenzylisoquinolines 297 in 23-54% yields via the quinodimethides (Scheme 53). On the other hand, 13-unsubstituted metho salts 298 furnished, on irradiation, the imino ketones 299 (Scheme 54) instead of spirobenzylisoquinolines through N-demethylation and oxidation via the quinodimethide... 

One of numerous examples of LOX-catalyzed cooxidation reactions is the oxidation and demethylation of amino derivatives of aromatic compounds. Oxidation of such compounds as 4-aminobiphenyl, a component of tobacco smoke, phenothiazine tranquillizers, and others is supposed to be the origin of their damaging effects including reproductive toxicity. Thus, LOX-catalyzed cooxidation of phenothiazine derivatives with hydrogen peroxide resulted in the formation of cation radicals [40]. Soybean LOX and human term placenta LOX catalyzed the free radical-mediated cooxidation of 4-aminobiphenyl to toxic intermediates [41]. It has been suggested that demethylation of aminopyrine by soybean LOX is mediated by the cation radicals and neutral radicals [42]. Similarly, soybean and human term placenta LOXs catalyzed N-demethylation of phenothiazines [43] and derivatives of A,A-dimethylaniline [44] and the formation of glutathione conjugate from ethacrynic acid and p-aminophenol [45,46],... 

The major biotransformations of pseudoephedrine hydrochloride are parahydroxylation, N-demethylation, and oxidative deamination.14 The proposed pathways for the metabolism of pseudoephedrine are shown in Figure 6. 

Cocaine-mediated hepatotoxicity has been associated with the conversion of cocaine to norcocaine and further oxidation products. The enzymes involved in in vitro hepatic oxidative N-demethylation of cocaine (192) were investigated (237), and two different enzymatic pathways appear to be important in the formation of the hepatotoxic metabolite. Cytochrome P-450 monooxygenases accomplish the direct N-demethylation of cocaine to norcocaine (194) as confirmed by induction and inhibition studies (Scheme 42). The second pathway for cocaine N-demethylation involves formation of cocaine /V-oxide (193) as an intermediate and two enzymes. A flavin-containing monooxygenase is first thought to convert cocaine to cocaine /V-oxide, followed by cytochrome P-450-... 

Scheme 42. Two pathways for the N-demethylation of cocaine by mammalian liver microsomal enzyme preparations.

Nicotine Resolution of racemates N-Demethylation, pyrrole oxidation N-Dealkylation, pyrrole oxidation, iminium formation... 

The reaction is not useful for N-demethylation because of slow rate and low yield. In fact, selective N-debenzylation is possible with this reagent. 

N-demethylation at the three N-methyl sites. In this regard, the 3-N-demethylation of caffeine to generate paraxanthine can serve as a particularly good in vivo indicator of the presence and activity of CYP1A2 (Fig. 4.7). In the case of phenacetin, CYP1A2 catalyzes N-deethylation to generate acetaminophen. Not unexpectedly, 1 A2 s selectivity toward heterocyclic aromatic substrates carries over to inhibitors of the enzyme. Furafylline (Fig. 4.7) is an example of a particularly potent 1A2 mechanism-based inhibitor. 

Miwa GT, Walsh JS, Kedderis GL, et al. The use of intramolecular isotope effects to distinguish between deprotonation and hydrogen atom abstraction mechanisms in cytochrome P-450- and peroxidase-catalyzed N-demethylation reactions. J Biol Chem 1983 258(23) 14445-14449. 

Galliani G, Nali M, Rindone B, et al. The rate of N-demethylation of N, N-dimethylanilines and N-methylanilines by rat-liver microsomes is related to their first ionization potential, their lipophilicity and to a steric bulk factor. Xenobiotica 1986 16(6) 511—517. 

Clement B, Zimmermann M. Hepatic microsomal N-demethylation of N-methylbenzamidine. N-d ealkylation vs N-oxygenation of amidines. Biochem Pharmacol 1987 36(19) 3127-3133. 

Sladek, N.E. and Mannering, G.J. (1969) Induction of drug metabolism. I. Differences in the mechanisms by which polycyclic hydrocarbons and phenobarbital produce their inductive effects on microsomal N-demethylating systems. Molecular Pharmacology, 5 (2), 174-185. 

Sutton, D., Butler, A.M., Nadin, L. and Murray, M. (1997) Role of CYP3A4 in human hepatic diltiazem N-demethylation inhibition of CYP3A4 activity by oxidized diltiazem metabolites. Journal of Pharmacology and Experimental Therapeutics, 282 (1), 294-300. 

Irradiation rraws-2-[3-(7V-methylamino)propyl] stilbene 89 results in the formation of 7V-methyl-l-benzyltetrahydro-2-benzazepine 90 as the only significant primary photoproduct (equation 26), which in turn undergoes secondary photochemical N-demethylation. The final mixture contains 90 (38%) and 91 (25%) at high (>95%) conversion. Intramolecular photoadditions of these (equations 24-26) secondary (aminoalkyl)-stilbenes are highly regioselective processes24. 

Metabolism Oxidation Glucuronidation Hydroxylation N-Demethylation Hydroxylation Plasma and hepatic esterases... 

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