Synthesis and characterization of adducts formed in the reactions of safrole 2′,3′-oxide with 2′-deoxyadenosine, adenine, and calf thymus DNA

Li Ching Shen, Su Yin Chiang, I. Ting Ho, Kuen Yuh Wu*, Wen-Sheng Chung

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Safrole (1) is a natural product found in herbs and spices. Upon uptake, it can be metabolized to safrole 2′,3′-oxide [(±)-SFO, 2], which can react with DNA bases to form DNA adducts. The reactions of 2 with 2′-deoxyadenosine (3) and adenine (8) under physiological conditions (pH 7.4, 37 °C) were carried out to characterize its possible adducts with adenine. Four adducts were isolated by reverse-phase liquid chromatography and their structures were characterized by UV/Vis, 1H and 13C NMR spectroscopy and MS. The reaction of 2 with 3 produced two regioisomers, N1γ-SFO-dAdo (4) and N 6γ-SFO-dAdo (5), in 4.2-4.5 % yield, and the reaction of 2 with 8 generated N3γ-SFO-Ade (9) and N9γ-SFO-Ade (10) in 1.0-2.4 % yield. Using HPLC-ESI-MS/MS, we traced the amounts of the four adducts formed when calf thymus DNA (10 mg) was treated with 2 (60 μmol) and the levels of 4, 5, and 9 were determined to be 2000, 170, and 660 adducts per 10 6 nucleotides, respectively. Adduct 10 was not detected under these conditions. These results suggested that stable DNA adducts of 2 were formed in vitro, and further studies on the formation of these DNA adducts in vivo may help to elucidate their role in safrole carcinogenicity. Safrole (1) is naturally present in plants and is banned for use in food additives. The genotoxicity of safrole 2′,3′-oxide 2, which is an in vivo metabolite of 1, has attractedinterest because of its structural similarity to other known epoxide carcinogens. In this work, adenine adducts of 2 have been synthesized and characterized.

Original languageEnglish
Pages (from-to)792-800
Number of pages9
JournalEuropean Journal of Organic Chemistry
Issue number4
DOIs
StatePublished - 30 Jan 2012

Keywords

  • Cancer
  • DNA adducts
  • DNA damage
  • Safrole

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