The role of cytochrome P-450 in the biological nuclear N-oxidation of aminoaza-heterocyclic drugs and related compounds

Gorrod, J. W.; Lam, S. P.

doi:10.1007/978-94-011-3112-4_10

Cited by 6 publications

(2 citation statements)

References 33 publications

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“…It was previously suggested that the conformation of 9-alkyladenines and 9-aralkyladenines is an important controlling factor for their NI-oxidation (3,7,8). Therefore, further substitution in the phenyl moiety of 9-benzyladenine may modify the conformation of the molecule in question, thus affecting the enzyme-substrate binding or enzyme selectivity; leading to a variation of metabolism.…”

Section: Quantitative Comparison Of Metabolismmentioning

confidence: 99%

“…As NI-oxidation of these substrates appears to be a detoxification process (6), it is important to establish the controlling factors. Among the possible controlling factors of the NI-oxidation of these adenine derivatives, it was believed that BA possesses a conformation favourable to the corresponding N-oxidase(s) (4,7). A recent investigation on the N 1-oxidation of isomeric 9-(nitrobcnzyl)adenines (NBAs) confirmed that further substitution in the benzyl moiety may greatly modulate the formation rate of NI-oxides from the substrates (8).…”

Section: Introductionmentioning

confidence: 99%

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Metabolism of 9-(2-chlorobenzyl)-, 9-(2-methylbenzyl)-and 9-(2-methoxybenzyl)-adenines by hamster hepatic microsomes

Liu

El-Ghomari

et al. 1997

Eur. J. Drug Metab. Pharmacokinet.

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It was previously found that 9-benzyladenine (BA) was extensively N1-oxidised by animal hepatic microsomes; further, mononitrosubstitution in the phenyl moiety of BA significantly modified the N1-oxidation rates of the corresponding substrates. In order to establish whether the electronic nature or a steric effect of the substituents in the phenyl moiety is the reason for the modification of N1-oxidation rate, the metabolism of some 2'-substituted 9-benzyladenines, i.e. 9-(2-chlorobenzyl)adenine (2CBA), 9-(2-methyl-benzyl)adenine (2MBA) and 9-(2-methoxybenzyl)adenine (2MOBA), by hamster hepatic microsomes was studied. It was found that the N1-oxide was still the major metabolite for 2CBA. However, only minor amounts of N1-oxides were formed during microsomal incubation with 2MBA and 2MOBA. On the other hand, in spite of the higher N1-oxidation rate of 2CBA, its total biotransformation rate was slightly lower than the other two substrates. Like other 9-aralkyladenines previously studied, dealkylation occurred for all three substrates. It was also found that another two metabolites formed in significant amounts in the incubates from both 2MBA and 2MOBA. These metabolites were not fully characterised and their structures unknown.

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Section: Quantitative Comparison Of Metabolismmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolism of 9-(2-chlorobenzyl)-, 9-(2-methylbenzyl)-and 9-(2-methoxybenzyl)-adenines by hamster hepatic microsomes

Liu

El-Ghomari

et al. 1997

Eur. J. Drug Metab. Pharmacokinet.

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

Hlavica

Lehnerer

2009

Patai's Chemistry of Functional Groups

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Introduction Chemical Aspects of the N ‐Oxygenation of the C  N Functionality Occurrence of N ‐Oxygenated C  N Functionalities in Natural and Synthetic Compounds and Biological Activity Metabolic in Vivo and in Vitro Formation of N ‐Oxygenated C  N Functionalities Enzymology of the Formation of N ‐Oxygenated C  N Functionalities Further Transformations of N ‐Oxygenated C  N Functionalities Conclusions

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Studies on the relationship between in vitro metabolism and certain physicochemical characteristics of some 9-alkyl-/9-aralkyl adenines

Liu

Lam

Gorrod

1997

Eur. J. Drug Metab. Pharmacokinet.

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Previous studies demonstrated that biological N1-oxidation occurred for some 9-alkyl-/9-aralkyladenines, but not for others, when mammalian hepatic microsomal incubates were used as enzyme source. In order to understand the mechanisms controlling the metabolic fate of these compounds, the relationship between N1-oxidation and certain physicochemical characteristics of these substrates was studied. It was found that there was no marked link between N1-oxidation and the computer predicted pKa values of the substances studied. However, a computer predicted LogP value in the range 1.3-4 seems to be the most favourable for N1-oxidation. The 1H-NMR and 13C-NMR spectroscopic characteristics of the substrates, which reflect certain electronic characteristics of the purine moiety, also showed a correlation with their N1-oxidation. The electronic effects of the substrates in relation to their metabolism was investigated using computer modelling techniques; the results showed that different substituents at the 9-position of adenine may modify the electronic characteristics of the purine moiety thus affecting their metabolism. The conformation of the substrates may also be an important controlling factor for their N1-oxidative metabolism.

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The role of cytochrome P-450 in the biological nuclear N-oxidation of aminoaza-heterocyclic drugs and related compounds

Cited by 6 publications

References 33 publications

Metabolism of 9-(2-chlorobenzyl)-, 9-(2-methylbenzyl)-and 9-(2-methoxybenzyl)-adenines by hamster hepatic microsomes

Metabolism of 9-(2-chlorobenzyl)-, 9-(2-methylbenzyl)-and 9-(2-methoxybenzyl)-adenines by hamster hepatic microsomes

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

Studies on the relationship between in vitro metabolism and certain physicochemical characteristics of some 9-alkyl-/9-aralkyl adenines

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