163088-94-6Relevant articles and documents
Reaction of α-Acetoxy-N-nitrosopyrrolidine with Deoxyguanosine and DNA
Wang, Mingyao,McIntee, Edward J.,Shi, Yongli,Cheng, Guang,Upadhyaya, Pramod,Villalta, Peter W.,Hecht, Stephen S.
, p. 1428 - 1434 (2007/10/03)
We investigated the reactions of α-acetoxy-N-nitrosopyrrolidine (α-acetoxyNPYR) with dGuo and DNA. α-AcetoxyNPYR is a stable precursor to the major proximate carcinogen of NPYR, α-hydroxyNPYR (3). Our goal was to develop appropriate conditions for the analysis of DNA adducts of NPYR formed in vivo. Products of the α-acetoxyNPYR-dGuo reactions were analyzed directly by HPLC or after treatment of the reaction mixtures with NaBH3CN. Products of the α-acetoxyNPYR-DNA reactions were released by enzymatic or neutral thermal hydrolysis of the DNA, then analyzed by HPLC. Alternatively, the DNA was treated with NaBH3CN prior to hydrolysis and HPLC analysis. The reactions of α-acetoxyNPYR with dGuo and DNA were complex. We have identified 13 products of the dGuo reaction - 6 of these were characterized in this reaction for the first time. They were four diastereomers of N2-(3-hydroxybutylidene)-dGuo (20,21), 7-(N-nitrosopyrrolidin-2-yl)Gua (2), and 2-(2-hydroxypyrrolidin-1-yl)deoxyinosine (12). Adducts 20 and 21 were identified by comparison to standards produced in the reaction of 3-hydroxybutanal with dGuo. Adduct 2 was identified by its spectral properties while adduct 12 was characterized by comparison to an independently synthesized standard. With the exception of adduct 2, all products of the dGuo reactions were also observed in the DNA reactions. The major product in both the dGuo and DNA reactions was N2-(tetrahydrofuran-2-yl)dGuo (10), consistent with previous studies. Several other previously identified adducts were also observed in this study. HPLC analysis of reaction mixtures treated with NaBH3CN provided improved conditions for adduct identification, which should be useful for in vivo studies of DNA adduct formation by NPYR.
Reactions of α-Acetoxy-N-nitrosopyrrolidine and α-Acetoxy-N-nitrosopiperidine with Deoxyguanosine: Formation of N2-Tetrahydrofuranyl and N2-Tetrahydropyranyl Adducts
Young-Sciame, Ruth,Wang, Mingyao,Chung, Fung-Lung,Hecht, Stephen S.
, p. 607 - 616 (2007/10/03)
The goal of this study was to compare the reactions of α-acetoxy-N-nitrosopyrrolidine (α-acetoxyNPYR) and α-acetoxy-N-nitrosopiperidine (α-acetoxyNPIP) with deoxyguanosine (dG). α-AcetoxyNPYR and α-acetoxyNPIP are stable precursors to the α-hydroxynitrosamines which are formed metabolically from NPYR and NPIP. These α-hydroxynitrosamines are believed to be the proximate carcinogens of NPYR and NPIP. NPYR and NPIP, although structurally similar, have remarkably different carcinogenic properties, and a comparison of the reactions of their metabolically activated forms with dG and ultimately DNA could provide insights on their mechanisms of carcinogenicity. Reactions of α-acetoxyNPYR and α-acetoxyNPIP with dG were carried out at 37 deg C and pH 7.0. The products were analyzed by HPLC and characterized by their spectral properties and by comparison to standards. In each reaction, one of the major products was a new type of dG adduct: N2-(tetrahydrofuran-2-yl)dG (THF-dG) from α-acetoxyNPYR and N2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)dG (THP-dG) from α-acetoxyNPIP. THF-dG was synthesized independently by reaction of either 2-chlorotetrahydrofuran 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 1H-NMR spectra. THF-dG was less stable than THP-dG, but could be readily converted to a stable derivative, N2-(4-hydroxybutyl)dG, by reaction with NaBH4. THF-dG and THP-dG were converted to dG and 2-hydroxytetrahydrofuran 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 α-acetoxynitrosamines; stable oxonium ion-derived electrophiles may also be involved in the formation of THF-dG and THP-dG. Comparisons of the yields of various adducts in the reaction of α-acetoxyNPYR and α-acetoxyNPIP with dG showed some major differences. Whereas yields of THF-dG and THP-dG were similar, adducts formed from open chain diazonium ion or related intermediates were formed more extensively from α-acetoxyNPYR than from α-acetoxyNPIP. Adducts formed from enal products of the two nitrosamines were also different. Adduct formation as characterized in this study may account for some of the contrasting carcinogenic properties of NPYR and NPIP.
