Metabolic N-oxygenation of 2,4-diamino-6-substituted pyrimidines

Abstract

Biological oxidation of 2,4-diamino-6-substituted pyrimidines have been studied using hepatic microsomes from various mammalian species. The nature of the enzyme(s) involved in the oxidation has been elucidated using various enzyme inhibitors and inducing agents. The 3-N-oxides were formed with 6-piperidino-, 6-diethylamino-, 6-methyl-, and 6-chloro-substituted 2,4-diaminopyrimidines: no evidence of 1-N-oxide formation was obtained. With the 6-hydroxy-, 6-amino-, and unsubstituted 2,4-diaminopyrimidines and melamine, no N-oxidative metabolite was detected. The differences in N-oxide formation was discussed in terms of the effect of substituents on tautomerism and electron distribution. The N-oxygenation was mediated via a cytochrome P450 dependent system.

EFSA provisional statement on a request form the European Commission related to melamine and structurally related to compounds such as cyanuric acid in protein‐rich ingredients used for food and feed

“…Biological oxidation of 2,4-diamino-6-substituted pyrimidines have been studied using hepatic microsomes from various mammalian species. With the 6-hydroxy-, 6-amino-, and unsubstituted 2,4-diaminopyrimidines and melamine, no N-oxidative metabolites were detected (El Ghomari and Gorrod, 1987).…”

N‐Oxidative Transformations ofCNGroups as Means of Toxification and Detoxification

“…Ascending paper chromatography 30 along with TLC was also used to identify N-oxide metabolites originating from organic compounds containing a pyridyl nucleus 31,32 . Finally, TLC has proved to be useful in the separation of N-oxides arising from metabolic transformation of pyridazines, pyrimidines and pyrazines 8,9 . Identification of trace amounts of metabolites was often aided by the application of radiolabeled compounds 21,32 permitting autoradiography of the TLC plates.…”

“…Reverse-phase HPLC has been used for the separation of aldoximes 45 , ketoximes 46 , amidoximes 14,47 52 and nitrones 3,26,53 55 . This method also served to identify Noxides derived from pyridines 7,29,31,56 63 , pyrimidines 8,9,16 , pyrazines 9 , pyridazines 9 and purines 64,65 ; the latter class of heteroaromatic N-oxides was analyzed on cationic exchange columns.…”

“…The antimalarial agent pyrimethamine, another 5-substituted 2,4-diaminopyrimidine, has been shown to be excreted in rat urine mainly as the 3-Noxide 106 . A series of 6-substituted analogues has been demonstrated to yield 3-N-oxides in liver microsomal fractions from various animal species without evidence of 1-N-oxide formation 8 .…”

Mutagenicity Testing of 9-N-Substituted Adenines and Their N-Oxidation Products

“…The metabolism of many of these compounds has been studied (1-3), and generally it has been observed that compounds used in clinical medicine are not genotoxic and are metabolized by oxidation at one or more nuclear nitrogens (6)(7)(8)(9)(10)(11)(12), whereas those produced by pyrolysis are potent mutagens (13) and are metabolized by N-hydroxylation of the exo amino group (14)(15)(16). This has led to the concept (1-3) that nuclear N-oxidation of aminoazaheterocycles is a detoxication process, whereas N-hydroxylation of the exo amino group is a toxication reaction (Fig.…”