title: Structural elucidation of a novel DNA-DNA cross-link of 1,2,3,4-diepoxybutane.
abstract: DNA-DNA cross-linking by 1,2,3,4-diepoxybutane (DEB) is considered the molecular basis for its potent cytotoxic and genotoxic effects. DEB reactions with DNA initially lead to N7-(2'-hydroxy-3',4'-epoxybut-1'-yl)-guanine monoadducts, which can then alkylate neighboring DNA bases to form bifunctional lesions. We recently reported the structures of four regioisomeric guanine-adenine adducts of DEB involving the N7 position of guanine and the N1, N3, N6, and N7 positions of adenine (Park, S., et al. (2004) Chemical Research in Toxicology 17, 1638-1651). In the present work, a novel bifunctional DNA lesion of DEB was identified as 1-(hypoxanth-1-yl)-4-(guan-7-yl)-2,3-butanediol (N1HX-N7G-BD). An authentic standard of N1HX-N7G-BD was prepared and structurally characterized by proton NMR, UV, and mass spectrometry. HPLC-ESI-MS/MS analyses of acid hydrolysates of DEB-treated calf thymus DNA revealed a peak that had the same retention time, MS/MS fragmentation, and UV spectrum as the authentic standard of N1HX-N7G-BD. We propose that N1HX-N7G-BD is formed by the hydrolytic deamination of previously reported 1-(aden-1-yl)-4-(guan-7-yl)-2,3-butanediol. Although N1HX-N7G-BD adducts are less abundant in DEB-treated DNA than the corresponding guanine-guanine cross-links, they may play a role in the induction of both AT and GC base pair mutations.
authors.affiliation: University of Minnesota Cancer Center and Department of Medicinal Chemistry, Minneapolis, Minnesota 55455, USA. trety@umn.edu
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
authors.forename: Alina
authors.initials: A
authors.lastname: Livshits
authors.forename: Soobong
authors.initials: S
authors.lastname: Park
authors.forename: Bimi
authors.initials: B
authors.lastname: Bisht
authors.forename: Melissa
authors.initials: M
authors.lastname: Goggin
mesh_terms: D002072:Butylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000138:chemical synthesis / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry*; D007042:Hypoxanthines / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: C519542:1-(hypoxanth-1-yl)-4-(guan-7-yl)-2,3-butanediol; D002072:Butylene Glycols; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004852:Epoxy Compounds; D007042:Hypoxanthines; C007366:diepoxybutane; D004247:DNA; C427203:calf thymus DNA