Reactions of estradiol-2,3-quinone with deoxyribonucleosides: possible insights in the reactivity of estrogen quinones with DNA.
Estrogen 2,3- and 3,4-quinones are reactive species toward nucleophiles and Michael acceptors. As such, they can bind to DNA and induce cellular damages. As an alkylation model, reactions of estradiol-2,3-quinone with deoxyribonucleosides were previously studied by mass spectrometry. In this work, estrogen-deoxyribonucleoside adducts were synthesized by reaction of 17beta-estradiol-2,3-quinone with deoxyguanosine or deoxyadenosine and analyzed by NMR and LC-MS(n)() in order to determine the structure and the stereochemistry of the resulting covalent adducts. Although estradiol- and estrone-2,3-quinones were previously thought to give mainly stable adducts, identification of depurinating adducts with both nucleosides, i.e., 2-OHE(2)-6(alpha,beta)-N7Gua and 2-OHE(2)-6(alpha,beta)-N7Ade, was unambiguously obtained. This is of particular interest since depurinating adducts are generated from DNA, and therefore, their amount should be correlated to the parallel formation of apurinic sites, which might play an important role in the cancer initiation process. Besides, a byproduct, i.e., 2-hydroxy-11-oxo-estradiol, corresponding to an unstable alkylation product of 2-hydroxyestradiol has been unambiguously identified and is indicative of a plausible addition process at the C9 position of catechol estrogens. The synthetic adducts will be useful as reference compounds to further elucidate the structure of adducts formed by reaction of estrogen metabolites with DNA or oligonucleotides.
Convert
Odile
O
Laboratoire de Chimie Structurale Organique et Biologique, CNRS UMR7613, UPMC, 4 place Jussieu, 75252 Paris Cedex 05, France. oconvert@ccr.jussieu.fr
Van Aerden
Christel
C
Debrauwer
Laurent
L
Rathahao
Estelle
E
Molines
Huguette
H
Fournier
Françoise
F
Tabet
Jean-Claude
JC
Paris
Alain
A
D002851:Chromatography, High Pressure Liquid; D003853:Deoxyribonucleosides / Q000737:chemistry*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D055672:Static Electricity; D013329:Structure-Activity Relationship
D003853:Deoxyribonucleosides; C049872:estradiol-2,3-O-quinone; D004958:Estradiol