Reaction of α-Acetoxy-N-nitrosopiperidine with Deoxyguanosine: Oxygen-Dependent formation of 4-Oxo-2-pentenal and a 1,N²-Ethenodeoxyguanosine Adduct

The six-membered heterocyclic nitrosamine N-nitrosopiperidine (NPIP) is an esophageal carcinogen in the rat whereas its five-membered homologue N-nitrosopyrrolidine (NPYR) is a liver carcinogen. These contrasting organospecificities may be due to differences between NPIP and NPYR in their metabolic activation to intermediates which bind to DNA. Previous studies have shown that the metabolic activation of NPYR to DNA binding products occurs through α-hydroxylation. DNA adducts of NPIP have not been characterized. Therefore, we began our studies by investigating the reaction of α-acetoxyNPIP with deoxyguanosine. A major adduct, detected by highperformance liquid chromatography with UV detection, was characterized by its UV, ¹H-NMR, and MS as 7-(2-oxopropyl)-5,9-dihydro-9-oxo-3-β-d-deoxyribofuranosylimidazo[1,2-a]purine. This 7-(2-oxopropyl)-substituted 1,N²-ethenodeoxyguanosine adduct was formed by reaction of 4-oxo-2-pentenal (3-acetylacrolein) with the 1 and N² positions of deoxyguanosine. Since the formation of 4-oxo-2-pentenal from α-acetoxyNPIP was unexpected, we investigated the solvolysis of α-acetoxyNPIP in more detail. Major products formed in incubations of α-acetoxyNPIP for 7-24 h in phosphate buffer (pH 7.0) at 37 °C included 4-oxo-2-pentenal (11-21% yield), 4-hydroxypentanal (18-22%), and 5-hydroxypentanal (27-29%). The formation of 4-oxo-2-pentenal required O₂. The results of this study demonstrate some unique features of the chemistry of α-acetoxyNPIP and the resulting deoxyguanosine adducts which may be related to the carcinogenic activity of NPIP.