title: Exocyclic deoxyadenosine adducts of 1,2,3,4-diepoxybutane: synthesis, structural elucidation, and mechanistic studies.
abstract: 1,2,3,4-Diepoxybutane (DEB) is considered the ultimate carcinogenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant present in urban air. Although it preferentially modifies guanine within DNA, DEB induces a large number of A --> T transversions, suggesting that it forms strongly mispairing lesions at adenine nucleobases. We now report the discovery of three potentially mispairing exocyclic adenine lesions of DEB: N(6),N(6)-(2,3-dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (compound 2), 1,N(6)-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine (compound 3), and 1,N(6)-(1-hydroxymethyl-2-hydroxypropan-1,3-diyl)-2'-deoxyadenosine (compound 4). The structures and stereochemistry of the novel DEB-dA adducts were determined by a combination of UV and NMR spectroscopy, tandem mass spectrometry, and independent synthesis. We found that synthetic N(6)-(2-hydroxy-3,4-epoxybut-1-yl)-2'-deoxyadenosine (compound 1) representing the product of N(6)-adenine alkylation by DEB spontaneously cyclizes to form 3 under aqueous conditions or 2 under anhydrous conditions in the presence of an organic base. Compound 3 can be interconverted with 4 by a reversible unimolecular pericyclic reaction favoring 4 as a more thermodynamically stable product. Both 3 and 4 are present in double stranded DNA treated with DEB in vitro and in liver DNA of laboratory mice exposed to 1,3-butadiene by inhalation. We propose that in DNA under physiological conditions, DEB alkylates the N-1 position of adenine in DNA to form N1-(2-hydroxy-3,4-epoxybut-1-yl)-adenine adducts, which undergo an S(N)2-type intramolecular nucleophilic substitution and rearrangement to give 3 (minor) and 4 (major). Formation of exocyclic DEB-adenine lesions following exposure to 1,3-butadiene provides a possible mechanism of mutagenesis at the A:T base pairs.
authors.affiliation: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Uthpala
authors.initials: U
authors.lastname: Seneviratne
authors.forename: Sergey
authors.initials: S
authors.lastname: Antsypovich
authors.forename: Melissa
authors.initials: M
authors.lastname: Goggin
authors.forename: Danae Quirk
authors.initials: DQ
authors.lastname: Dorr
authors.forename: Rebecca
authors.initials: R
authors.lastname: Guza
authors.forename: Adam
authors.initials: A
authors.lastname: Moser
authors.forename: Carrie
authors.initials: C
authors.lastname: Thompson
authors.forename: Darrin M
authors.initials: DM
authors.lastname: York
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
mesh_terms: D020029:Base Pairing; D002070:Butadienes / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000138:chemical synthesis* / Q000737:chemistry; D003839:Deoxyadenosines / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry*; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
chemical_list: C550994:1,N6-(1-hydroxymethyl-2-hydroxypropan-1,3-diyl)-2'-deoxyadenosine; C550993:1,N6-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine; D002070:Butadienes; D018736:DNA Adducts; D003839:Deoxyadenosines; D004852:Epoxy Compounds; C007366:diepoxybutane; C031763:1,3-butadiene