Facile syntheses of O2-[4-(3-pyridyl-4-oxobut-1-yl]thymidine, the major adduct formed by tobacco specific nitrosamine 4-methylnitrosamino-1- (3-pyridyl)-1-butanone (NNK) in vivo, and its site-specifically adducted oligodeoxynucleotides

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O2-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O2-POB- dThd) is the most persistent adduct detected in the lung and liver of rats treated with tobacco specific nitrosamines: N′-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). It is an important biomarker to assess the human exposure to these carcinogens. The only synthetic method reported for O2-POB-dThd requires repeated HPLC purifications and could only be used to prepare an analytical standard due to very low yield (0.4%). We have developed for the first time a regioselective and efficient method for the total synthesis of O2-POB-dThd and its site-specifically adducted oligonucleotides. The main step in the synthesis of O2-POB-dThd was achieved by a novel method. The treatment of O 2-5′-anhydrothymidine with the sodium salt of 4-(1,3-dithian-2-yl)-4-(3-pyridyl)butan-1-ol gave exclusively the O 2-alkylated adduct, which was deprotected in one step to furnish the desired O2-POB-dThd in excellent yield. The product was characterized by NMR (1H and 13C), high-resolution MS, and HPLC analysis. This work provided for the first time a reliable method for large scale total synthesis of O2-POB-dThd that allowed for solid state site-specifically adducted oligomer synthesis. The O2-POB-dThd was converted to its phosphoramidite and subsequently used for the synthesis of oligodeoxynucleotides by standard methods. The oligomers were characterized by MS and HPLC analysis. These oligomers will facilitate the elucidation of the mutagenic potential of the O2-POB-dThd adduct, which will provide further insight into the role of tobacco-specific nitrosamines in inducing cancers in smokers.

Original languageEnglish (US)
Pages (from-to)960-967
Number of pages8
JournalChemical research in toxicology
Issue number6
StatePublished - Jun 20 2011

All Science Journal Classification (ASJC) codes

  • Toxicology

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