A-Demethylation

A51568A (A/-demethyl-vancomycin), B Nocardia orientalis N RRL 15232 1982 Lilly 39,40... 

An a-demethylated product (81) is formed unexpectedly when the tetrasubstituted pyrrole... 

Smith RV, Erhardt PW, Leslie SW. Microsomal O-demethylation, A-demethyl-ation and aromatic hydroxylation in the presence of bisulfite and dithiothreitol. Res Commun Chem Path Pharmacol 1975 12 181-4. 

Londry KL, PM Fedorak (1993) Use of fluorinated compounds to detect aromatic metabolites from m-cresol in a methanogenic consortium evidence for a demethylation reaction. Appl Environ Microbiol 59 2229-2238. 

The principal degradation products of bifenox are the free acid, 5-(2,4-dichlorophenoxy)-2-nitrobenzoic acid, and the amino derivatives, methyl 5-(2,4-dichlorophenoxy)anthranilate and its free acid, in flooded soil. A free acid is observed in nonflooded soil. When [ " C]chlomethoxfen was used to treat rice field soil, chlomethoxfen was extensively transformed into unextractable products with organic solvents however, the amine, the A-demethylated compound and the formyl-amino and acetylamino compounds were isolated and identified as the metabolites of chlomethoxfen. ... 

Since, based on the historical data, complete kinetic regioselectivity was unlikely to be achieved, our attention was focused on the possibility of a demethylation followed by an N-methylation recycle (Scheme 6.15). Unfortunately, the attempted... 

Amoxapine is a demethylated metabolite of loxapine and, as a result of its postsynaptic receptor DA-blocking effects, may be associated with extra-pyramidal side effects. 

A A,A-dimethylcarboxamido group attached to other aromatic systems can be hydrolyzed enzymatically as demonstrated by the metabolism of the ring-opened 1,4-benzodiazepine derivative 4.84 in dogs and rats [53], Here also, hydrolysis was shown to proceed via the secondary and primary amide formed by A-demethylation. 

Our next examples concern ring-substituted succinimides. 2-Phenylsuc-cinimide (4.185), the A-demethylated metabolite of the antiepileptic drug phensuximide, was found to be a better substrate of DHPase than succinimide itself. Two ring-opened metabolites are conceivable, 3-phenylsuccin-amic acid (4.186) and 2-phenylsuccinamic acid (4.187), but only the latter was formed enzymatically. 2-Phenylsuccinimide is chiral, and ring-opening... 

TMPase acts to dephosphorylate both TMP and its precursor dUMP, forming a mixture of TdR and 2 -deoxyuridine (UdR). As a starting material for zidovudine synthesis, TdR must be essentially free of this impurity, which would pass through the manufacturing process to form a demethylated analogue of zidovudine. Separation of TdR and UdR requires difficult and costly downstream processing hence, the key to a commercial process is metabolic engineering to minimize biosynthetic UdR. 

The metabolites of ondansetron have been examined in urine and bile from rat and dog. The major pathways for metabolism of ondansetron are A-demethylation and hydroxylation Scheme 7.7). However, whereas A-de-methylation predominates in dog, this is only a minor metabolic route in rat. Hydroxylation may occur at the 6, 7 or 8 position in the carbazolone ring. Hydroxy metabolites of ondansetron are excreted predominantly as glucuronide or sulphate conjugates. Studies with immobilised glucuronyl-transferase (Heath, S.E., personal communication) have demonstrated that O- and A-glucuronidation of ondansetron metabolites may occur. 

Rajagopal et al. (1984) used numerous compounds to develop a proposed pathway of degradation of aldicarb in soil. These compounds included aldicarb oxime, A-hydroxymethyl aldicarb, A-hydroxymethyl aldicarb sulfoxide, A-demethyl aldicarb sulfoxide, A-demethyl aldicarb sulfone, aldicarb sulfoxide, aldicarb sulfone, A-hydroxymethyl aldicarb sulfone, aldicarb oxime sulfone, aldicarb sulfone aldehyde, aldicarb sulfone alcohol, aldicarb nitrile sulfone, aldicarb sulfone amide, aldicarb sulfone acid, aldicarb oxime sulfoxide, aldicarb sulfoxide aldehyde, aldicarb sulfoxide alcohol, aldicarb nitrile sulfoxide, aldicarb sulfoxide amide, aldicarb sulfoxide acid, elemental sulfur, carbon dioxide, and water. Mineralization was more rapid in aerobic surface soils than in either aerobic or anaerobic subsurface soils. In surface soils (30 cm depth) under aerobic conditions, half-lives ranged from 20 to 361 d. In subsurface soils (20 and 183 cm depths), half-lives under aerobic and anaerobic conditions were 131-233 and 223-1,130 d, respectively (Ou et al, 1985). The reported half-lives in soil ranged from approximately 70 d (Jury et ah, 1987) to several months (Jones et al, 1986). Bromilow et al. (1980) reported the half-life for aldicarb in soil to be 9.9 d at 15 °C and pH 6.34-7.0. 

Plant In strawberries, diphenamide was transformed via A-demethylation yielding N-methyl-2,2-diphenylacetamide (Golab et al., 1966). 

Plant. Degrades to a demethylated intermediate which subsequently is degraded to the aniline moiety (possibly 3-trifluoromethylaniline) (Hartley and Kidd, 1987 Humburg et al, 1989). Duke et al. (1991) reported that fluometuron degrades in plants via the following degradative pathway fluometuron to TV-methyl-A -(3-(trifluoromethyl) phenyl) urea which undergoes demethylation to... 

To discern the ion-radical nature of reactions, the so-called intramolecular and intermolecular proton/deuterium isotope effects may be of use. Baciocchi et al. (2005) revealed ion-radical mechanism for A-demethylation of A,A-dimethylanilines, (CH3)2NAr, by phthalimide-A-oxyl radical (Scheme 4.14). In this reaction, ( e/ D)intra values were derived for reactivity of (CD3)(CH3)NAr, whereas ( H/ D)inter was referred for the reactivity of (CD3)2NAr. The values of (A e/ D)intra were found to be always different and higher than These results, although are incompat-... 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

Apparently A-demethylations can occur in cells other than liver microsomes, since the demethylation of A -methyl-3 -deoxyadenosine (XXVTI) to... 

The A -demethylation pathway is common to the metabolism of Ml 25 (Vllf) and morphine, both drugs being converted to secondary amines by liver micro-somes under the same condition [55]. Reaction rates were depressed when microsomes from rats repeatedly treated with Ml25 or morphine were used. In the same work, rats were-shown to become tolerant to the pharmacological effects of M125 (shock avoidance and tail clip tests) and cross tolerance to morphine was also found. 

For example, PINO (i.e. >N—O"), generated from HPI by oxidation with Pb(OAc)4 (cf. Scheme 7) or by laser flash photolysis of (t-BuO)2 (cf. Scheme 5) at 266 nm, has been investigated in the oxidative A-demethylation of 4-X-substimted-Af,Af-dimethylanilines (X-DMAs) (Scheme 11). ... 

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