Oxidative reactions metabolic identification

N, O-Diacylated or O-alkylated N-hydroxysulfonamides release nitroxyl (HNO) upon hydrolysis or metabolic dealkylation, as determined by gas chromatographic identification of nitrous oxide in the reaction headspace [27-29, 38]. Scheme 7.5 depicts the decomposition of a representative compound (7) to a C-acyl nitroso species that hydrolyzes to yield HNO. Either hydrolysis or metabolism removes the O-acyl or O-alkyl group to give an N-hydroxy species that rapidly decomposes to give a sulfinic acid and an acyl nitroso species. This C-acyl nitroso species (8) hydrolyzes to the carboxylic acid and HNO (Scheme 7.5). These compounds demonstrate the ability to relax smooth muscle preparations in vitro and also inhibit aldehyde dehydrogenase, similar to other HNO donors [27, 29]. 

Formation of a lactam as a late metabolite is also possible, as documented by the identification of an important and novel lactam metabolite of the antimalarial drug primaquine (11.148) [161]. When 11.148 was incubated with hamster liver fractions for periods of up to 1 d in the absence of added cofactors, oxidative deamination at both amino groups was the primary metabolic reaction. The metabolite resulting from loss of the primary amino group was further oxidized to the carboxylic acid, which was recovered partly as such and partly as the lactam 11.149. 

Another consequence of these findings is that the same adduct can be formed by a free radical mediated pathway from MAB following a one electron oxidation by peroxides as that formed from methylol or me thimine by a two electron oxidation catalyzed by cytochrome P450. Clearly identification of the GSH adducts of carcinogens in vivo may not distinguish both metabolic activation systems. It is also still not clear whether cytochrome P450 and peroxidases form common intermediates during N-demethylation reactions (22-24). 

Following the identification of the benzophenones (Fig. 2, IX, X and XII) as metabolic products of P. patulum, the reasonable and attractive hypothesis was advanced that griseofulvin biosynthesis proceeded by the pathway acetate-malonate -> (VIII) -> (IX) (X) -> (XII) (XIV) -> (XI) -> (I R = Cl) it received some support from the fact that the reactions (XII) -> (XIV) -> (XI) and (XI) -> (I R = Cl) had already been achieved in vitro by oxidative phenol radical coupling and stereospecific selective catal)d ic reduction respectively for review see Grove (1964). 

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