REACTIONS OF ALPHA-ACETOXY-N-NITROSOPYRROLIDINE AND ALPHA-ACETOXY-N-NITROSOPIPERIDINE WITH DEOXYGUANOSINE - FORMATION OF N-2-TETRAHYDROFURANYL AND N-2-TETRAHYDROPYRANYL ADDUCTS

The goal of this study was to compare the reactions of alpha-acetoxy-N -nitrosopyrrolidine (alpha-acetoxyNPYR) and alpha-acetoxy-N-nitrosopip eridine (alpha-acetoxyNPIP) with deoxyguanosine (dG). alpha-AcetoxyNPY R and alpha-acetoxyNPIP are stable precursors to the alpha-hydroxynitr osamines which are formed metabolically from NPYR and NPIP. These alph a-hydroxynitrosamines are believed to be the proximate carcinogens of NPYR and NPIP. NPYR and NPIP, although structurally similar, have rema rkably different carcinogenic properties, and a comparison of the reac tions of their metabolically activated forms with dG and ultimately DN A could provide insights on their mechanisms of carcinogenicity. React ions of alpha-acetoxyNPYR and alpha-acetoxyNPIP with dG were carried o ut at 37 degrees C and pH 7.0. The products were analyzed by HPLC and characterized by their spectral properties and by comparison to standa rds. In each reaction, one of the major products was a new type of dG adduct: N-2-(tetrahydrofuran-2-yl)dG (THF-dG) from alpha-acetoxyNPYR a nd N-2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)dG (THP-dG) from alpha-acetox yNPIP. THF-dG was synthesized independently by reaction of either 8-ch lorotetrahydrofuran or 2,3-dihydrofuran with dG. Similarly, THP-dG was prepared by reaction of 2-chloro-3,4,5,6-tetrahydro-2H-pyran with dG. The structures of THF-dG and THP-dG were established by their UV and H-1-NMR spectra. THF-dG was less stable than THP-dG, but could be read ily converted to a stable derivative, N-2-(4-hydroxybutyl)dG, by react ion with NaBH4. THF-dG and THP-dG were converted to dG and 2-hydroxyte trahydrofuran or 2-hydroxy-3,4,5,6-tetrahydro-2H-pyran, respectively, upon neutral thermal or acid hydrolysis. This reaction was found to be reversible, with the adducts being produced in substantial amounts by reaction of 2-hydroxytetrahydrofuran or 2-hydroxy-3,4,5,6-tetrahydro- 2H-pyran with dG. The latter reaction accounts for part of the THF-dG and THP-dG produced from the alpha-acetoxynitrosamines; stable oxonium ion-derived electrophiles may also be involved in the formation of TH FdG and THP-dG. Comparisons of the yields of various adducts in the re action of alpha-acetoxyNPYR and alpha-acetoxyNPIP with dG showed some major differences. Whereas yields of THF-dG and THP-dG were similar, a dducts formed from open chain diazonium ion or related intermediates w ere formed more extensively from alpha-acetoxyNPYR than from alpha-ace toxyNPIP. Adducts formed from enal products of the two nitrosamines we re also different. Adduct formation as characterized in this study may account for some of the contrasting carcinogenic properties of NPYR a nd NPIP.