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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Reactions of alpha-acetoxy-N-nitrosopyrrolidine and alpha-acetoxy-N-nitrosopiperidine with deoxyguanosine: formation of N2-tetrahydrofuranyl and N2-tetrahydropyranyl adducts.

The goal of this study was to compare the reactions of alpha-acetoxy-N-nitrosopyrrolidine (alpha-acetoxyNPYR) and alpha-acetoxy-N-nitrosopiperidine (alpha-acetoxyNPIP) with deoxyguanosine (dG). alpha-AcetoxyNPYR and alpha-acetoxyNPIP are stable precursors to the alpha-hydroxynitrosamines which are formed metabolically from NPYR and NPIP. These alpha-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 alpha-acetoxyNPYR and alpha-acetoxyNPIP with dG were carried out at 37 degrees 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 alpha-acetoxyNPYR and N2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)dG (THP-dG) from alpha-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 alpha-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 alpha-acetoxyNPYR and alpha-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 alpha-acetoxyNPYR than from alpha-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.[1]


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