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Synthesis and Characterization of Adducts Formed in the Reactions of Safrole 2′,3′‐Oxide with 2′‐Deoxyadenosine, Adenine, and Calf Thymus DNA
Author(s) -
Shen LiChing,
Chiang SuYin,
Ho ITing,
Wu KuenYuh,
Chung WenSheng
Publication year - 2012
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201101384
Subject(s) - safrole , chemistry , adduct , deoxyadenosine , deoxyguanosine , dna , stereochemistry , yield (engineering) , high performance liquid chromatography , nucleotide , medicinal chemistry , organic chemistry , biochemistry , chromatography , materials science , metallurgy , gene
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, 1 H and 13 C NMR spectroscopy and MS. The reaction of 2 with 3 produced two regioisomers, N 1γ‐SFO‐dAdo ( 4 ) and N 6 γ‐SFO‐dAdo ( 5 ), in 4.2–4.5 % yield, and the reaction of 2 with 8 generated N 3γ‐SFO‐Ade ( 9 ) and N 9γ‐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.