Modification of guanine derivatives by reduced 2-nitroimidazoles.
Misonidazole, after reduction to the hydroxylamine derivative, was found to react with guanosine in aqueous solution at pH 7. The guanosine product was isolated and was assigned a structure having a new 5-membered ring with a -CHOH-CHOH-linkage between the N-1 and N-2 positions of guanine. Removal of the sugar residue from the guanosine product by acid hydrolysis resulted in the corresponding guanine derivative, which was also made by reacting guanine with reduced misonidazole. In aqueous solution at pH 11, the guanine product was quantitatively converted to guanine within 20 min. A number of N-1-substituted 2-nitroimidazoles and 2-nitroimidazole reacted with guanosine in an analogous manner, giving rise to the same product as misonidazole, indicating that the C-4-C-5 fragment from the imidazoles is involved in the modification. Neither misonidazole nor its amine or hydrazo derivatives reacted with guanosine. Reduced misonidazole reacted with N-2-methyl guanosine, whereas with N-1-methyl guanosine a reaction was not detected. The identity of Structure I was confirmed by comparison with an authentic sample of Structure I that was prepared by reacting guanosine with glyoxal. Reactions such as the modification of guanine provide a possible molecular mechanism for the cytotoxic and neurotoxic properties of misonidazole.
D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D006147:Guanine / Q000031:analogs & derivatives*; D006151:Guanosine / Q000378:metabolism; D008920:Misonidazole / Q000378:metabolism; D009593:Nitroimidazoles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet
D009593:Nitroimidazoles; D006151:Guanosine; D006147:Guanine; D008920:Misonidazole