Structural elucidation of a novel DNA-DNA cross-link of 1,2,3,4-diepoxybutane.
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.
Tretyakova
Natalia
N
University of Minnesota Cancer Center and Department of Medicinal Chemistry, Minneapolis, Minnesota 55455, USA. trety@umn.edu
Livshits
Alina
A
Park
Soobong
S
Bisht
Bimi
B
Goggin
Melissa
M
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
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