Chemical properties of the ultimate metabolites of 2-amino-5-phenylpyridine (PHE-P-1) and its orthomethyl derivative

Abstract The reactivity of the N -acetoxy metabolite of 2-amino-5-phenylpyridine (Phe-P-1), a pyrolysis product of phenylalanine, towards 2′-deoxyguanosine (dG), 2′-deoxyguanosine-3′-monophosphate (dGMP) and DNA was studied and compared with that of the ortho -methyl derivative. Reaction of 2-acetoxyamino-5-phenylpyridine ( N -OAc-APP) with dG resulted in substitution at the 8-position of this nucleoside by the ortho carbon of the amine. The major reaction, however, was acetylation of dG. In contrast, 2-acetoxyamino-3-methyl-5-phenylpyridine ( N -OAc-MeAPP) mainly attacked the 8-position of dG by the exocyclic nitrogen and hardly any acetylation of the nucleoside occurred. The adducts were chromatographically isolated and characterized by their mass and NMR spectra. Upon reaction of N -acetoxy compounds with DNA and dGMP, formation of the same adducts was observed, besides the formation of minor amounts of unidentified compounds, as was established by 32 P-postlabelling analysis. The amount of DNA-bound amine, formed by the interaction of N -OAc-APP with DNA, was ~15 times smaller than that observed after the reaction with the corresponding ortho -methyl derivative under the same conditions.