title: Synthesis of C8-N-Arylamine-Modified 2'-Deoxyguanosine-5'-Triphosphates and Their Effects on Primer Extension by DNA Polymerases.
abstract: C8-N-arylamine adducts of 2'-deoxyguanosine (2'-dG) play an important role in the induction of the chemical carcinogenesis caused by aromatic amines. C8-N-acetyl-N-arylamine dG adducts that differ in their substitution pattern in the aniline moiety were converted by cycloSal technology into the corresponding C8-N-acetyl-N-arylamine-2'-deoxyguanosine-5'-triphosphates and C8-NH-arylamine-2'-deoxyguanosine-5'-triphosphates. Their conformation preference has been investigated by NOE spectroscopy and DFT calculations. The substrate properties of the C8-dG adducts were studied in primer-extension assays by using Klenow fragment exo(-) of Escherichia coli DNA polymerase I and human DNA polymerase β. It was shown that the incorporation was independent of the substitution pattern in the aryl moiety and the N-acetyl group. Although the triphosphates were poor substrates for the human polymerases, they were incorporated twice before the termination of the elongation process occurred; this might demonstrate the importance of C8-N-arylamine-2'-deoxyguanosine-5'-triphosphates in chemical carcinogenesis.
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Höfler
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Sarac
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, Hamburg University, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany. chris.meier@chemie.uni-hamburg.de.
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
mesh_terms: D000586:Amination; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D063646:Carcinogenesis / Q000139:chemically induced; D004256:DNA Polymerase I / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D011122:Polyphosphates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D011122:Polyphosphates; D004256:DNA Polymerase I; D004259:DNA-Directed DNA Polymerase; D003849:Deoxyguanosine; C005692:triphosphoric acid; C023650:aniline
keywords: DNA damage; DNA polymerases; aromatic amines; carcinogenesis; conformation analysis; nucleotides