- Synthesis of site-specific damaged DNA strands by 8-(acetylarylamino)- 2′-deoxyguanosine adducts and effects on various DNA polymerases
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Beside the predominately found 8-(arylamino)-2′-dG, 8-(acetylarylamino) damages within DNA-strands may also play an important role in the induction of chemical carcinogenesis. A synthesis pathway leading to these 8-(acetylarylamino)-dG adducts using different aromatic amines has been optimized. The 8-modified dGs were converted into the corresponding phosphoramidites and site-specifically incorporated into different oligonucleotides leading to DNA strands. Lesion-bearing hybrids of these damaged DNA-strands with complementary oligonucleotides were used to study their melting properties and their circular dichroism spectra. It was shown that no EcoRI restriction took place with the damage inside the cleavage site. Finally, three different DNA polymerases were used for primer extension studies. C8-NAc-Arylamine adducts of 2′-deoxyguanosine with various aromatic amines were synthesized by using cross-coupling reactions and converted into 3′-phosphoramidites. Site-specific damaged NarI-, EcoRI- and 20mer-oligonucleotides were prepared by automated DNA-synthesis. Biophysical properties, restriction endonuclease studies and DNA-polymerase assays were performed. Copyright
- Krueger, Sarah,Meier, Chris
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p. 1158 - 1169
(2013/04/10)
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- A new short and efficient synthetic route to C8-N-acetylarylamine 2′-deoxyguanosine phosphoramidites
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In addition to their C8-NH-arylamine-dG counterparts, C8-N-acetylarylamine adducts of 2′-deoxyguanosine (2′-dG) play an important role in the possible induction of chemical carcinogenesis. A new synthetic pathway of this adduct type using different aromatic amines has been developed following most probably an electrophilic amination reaction. These adducts can be converted into the corresponding phosphoramidites for incorporation into oligonucleotides. Georg Thieme Verlag Stuttgart.
- Boege, Nicolas,Krueger, Sarah,Schroeder, Marcus,Meier, Chris
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p. 3907 - 3914
(2008/09/18)
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- Synthesis of N-acetoxy-N-benzoyl-2-aminofluorene, an ultimate carcinogen by LTA oxidation of α-phenyl-N-(2-aminofluorenyl)nitrone, and N-(2′-deoxyguanosin-8-yl)-2-aminofluorene
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The rearrangement of a new α-phenyl-N-(2-aminofluorenyl)nitrone (8) to a new ultimate carcinogen, N-acetoxy-N-benzoyl-2-aminofluorene (9) is achieved in a lead tetraacetate (LTA) oxidation reaction. Compound 9 reacts with deoxyguanosine (dG) at pH 7.0 to give N-(benzoyl)-N-(deoxyguanosin-8-yl)-2-aminofluorene (10). Subsequent debenzoylation with the heterogeneous system (sodium carbonate/methanol) leads to the C8-adduct, N-(2′-deoxyguanosin-8-yl)-2-aminofluorene (11).
- Mallesha,Ravi Kumar,Rangappa
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p. 2415 - 2418
(2007/10/03)
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- Mutagenicity in Salmonella typhimurium TA98 and TA100 of nitroso and respective hydroxylamine compounds
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Five aromatic nitroso compounds were prepared and their mutagenicity in Salmonella typhimurium strains TA98 and TA100 compared with that of the corresponding hydroxylamines and the previously studied nitroarenes. A remarkable correspondence of the dose-response curves was observed between the nitroso and the respective hydroxylamine compounds. This effect could be observed in TA98 and TA100. It was only marginally dependent on the metabolical activation by rat liver S9-mix. Even the presence of a bulky alkyl substituent either near to the functional group, or far away from it, previously shown to considerably influence the mutagenic properties of nitroarenes, does not remarkably affect the properties of the nitroso and hydroxylamine species. The similarity between the latter two is likely to be due to a fast reduction of the nitrosoarenes to the hydroxylamine species under the test conditions. It seems that enzymes are not responsible for that reduction step, because sterical crowding near the functional group does not influence that behaviour. The test results of the aromatic hydroxylamines bearing a bulky substituent show that there are at least two ways to influence the mutagenicity of an aromatic nitro compound by such a group. A substituent near the functional group (ortho-position) disturbs the enzymatic reduction of the nitro group, because 3-tert-butyl-4-hydroxylaminobiphenyl and its corresponding nitroso compound are highly mutagenic, whereas 3-tert-butyl-4-nitrobiphenyl was previously shown to be inactive even after addition of S9-mix. In contrast, 4′-tert-butyl-4-hydroxylaminobiphenyl with the tert-butyl group "far away" from the hydroxylamino functionality clearly shows decreased mutagenic activity suggesting a different influence of a substituent in that position. In addition, the substance shows only little cell toxicity even at higher concentrations. Both effects could be due to a reduced effective dose of the hydroxylamine in the cells compared to the non-alkylated compound, caused by a faster degradation of the hydroxylamine or a hindered interaction between that substance and the cells.
- Haack, Torsten,Erdinger, Lothar,Boche, Gernot
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p. 183 - 193
(2007/10/03)
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- Formation and reactions of N7-aminoguanosine and derivatives
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Arylamines are mutagens and carcinogens and are thought to initiate tumors by forming adducts with DNA. The major adducts are C8-guanyl, and we have previously suggested a role for guanyl-N7 intermediates in the formation process. N7-Aminoguanosine (Guo) was synthesized and characterized, with the position of the NH2 at N7 established by two- dimensional rotating frame Overhauser enhancement NMR spectroscopy. In DMF, N7-NH2Guo formed C8-NH2Guo and the cyclic product C8:5'-O-cycloGuo. In aqueous media, these products were formed along with 8-oxo-7,8-dihydroGuo, N7-NH2guanine, and a product characterized as a purine 8,9-ring-opened derivative (N-aminoformamidopyrimidine). The rate of aqueous decomposition of N7-NH2Guo increased with pH, with a t( 1/2 ) of 10 h at pH 7 and a t( 1/2 ) of 2 h at pH 9. The rate of migration of NH2 from N7 to C8 is fast enough to explain the formation of C8-NH2Guo from the reaction of 2,4- dinitrophenoxyamine with Guo but not the formation of C8-(arylamino)Guo in the reaction of Guo with aryl hydroxylamine esters; however, the fluorenyl moiety may facilitate the proposed rearrangement by stabilizing an incipient negative charge in the transfer. In the reaction of Guo with N-hydroxy-2- aminofluorene and acetylsalicylic acid, a peak with the mass spectrum expected for N7-(2-aminofluorenyl)Guo was detected early in the reaction and was distinguished from C8-(2-aminofluorenyl)Guo. NMR experiments with [8- 13C]Guo also provided some additional support for transient formation of N7-(2-aminofluorenyl)Guo. We conclude that a guanyl-N7 intermediate is reasonable in the reaction of activated arylamines with nucleic acids, although an exact rate of transfer of an N7-arylamine group to the C8 position has not yet been quantified. The results provide an explanation for the numerous products associated with modification of DNA by activated arylamines. However, the contribution of 'direct' reaction at the guanine C8 atom cannot be excluded.
- Guengerich, F. Peter,Mundkowski, Ralf G.,Voehler, Markus,Kadlubar, Fred F.
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p. 906 - 916
(2007/10/03)
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Model compound 3 in which the protected guanosine moiety is linked to the carcinogen (N-acetyl-N-hydroxy)-2-aminofluorene has been prepared and studied in various solvolytic conditions. The intramolecular reaction leads notably to the arylamidation of the
- Defrancq, Eric,Leterme, Anne,Pelloux, Nadia,Lhomme, Marie-France,Lhomme, Jean
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p. 5725 - 5736
(2007/10/02)
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- Arylhydroxamic Acid Bioactivation via Acyl Group Transfer. Structural Requirements for Transacylating and Electrophile-Generating Activity of N-(2-Fluorenyl)hydroxamic Acids and Related Compounds
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The synthesis of a series of 12 N-(2-fluorenyl)hydroxamic acids, N-(2-fluorenyl)-N-hydroxyureas, and N-(2-fluorenyl)-N-hydroxycarbamates is reported.The compounds were evaluated for their ability to serve as substrates for a partially purified hamster hepatic arylhydroxamic acid N,O-acyltransferase preparation.Transacylating activity was measured spectrophotometrically with 4-aminoazobenzene as the acyl group acceptor, and electrophile-generating activity was quantified by the N-acetylmethionine trapping assay.Only the N-acetyl, N-propionyl, and N-methoxyacetyl derivatives exhibited relatively high levels of activity as measured by either of the assay methods.These results are generally consistent with previously reported conclusions regarding the steric and electronic characteristics of acyl groups that are required for activation by this enzyme system.N,O-Acyltransferase inactivation by N-hydroxy-2-acetamidofluorene depressed the bioactivation of the N-acetyl compound to a greater extent than either the N-propionyl or N-methyloxyacetyl derivative.
- Yeh, Heui-mei,Hanna, Patrick E.
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p. 842 - 846
(2007/10/02)
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