Conformational analysis of 9-substituted adenines in relation to their microsomal N1-oxidation.
Metabolic N-oxidation of adenine, 9-methyladenine, 9-benzyladenine, 9-benzhydryladenine and 9-trityladenine has been investigated using hepatic microsomes from hamster, guinea-pig, rabbit, mouse, rat, and dog. N1-Oxide formation occurs with 9-benzyladenine and 9-benzhydryladenine using liver preparations of all species examined, although to different extents. The N-oxidase activity was found, amongst rodents, in the order hamster greater than mouse greater than rabbit greater than rat greater than guinea-pig. Microsomal preparations from dog liver contained a small quantity of P-450 and yet produced a relatively large amount of the N-oxides, possibly indicating that other cytochromes in addition to P-450 may be involved in the N-oxidation of these compounds. The most favourable conformations of these 9-substituted analogues have been established using computer graphics modelling and 1H NMR techniques. Results obtained confirmed the importance of the stereochemical properties of these compounds in relation to N1-oxidation. These observations substantiate and extend our previous findings on the electronic, lipophilic, and stereochemical factors affecting the N-oxidation of adenine derivatives.
Lam
S P
SP
Chelsea Department of Pharmacy, King's College London, University of London, UK.
Barlow
D J
DJ
Gorrod
J W
JW
D000225:Adenine / Q000031:analogs & derivatives* / Q000032:analysis* / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D004285:Dogs; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013237:Stereoisomerism
D000225:Adenine