Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate
AbstractMechanistic insights into the reaction of an estrogen o-quinone with deoxyguanosine has been further investigated using high level density functional calculations in addition to the use of 4-hyroxycatecholestrone (4-OHE1) regioselectivity labeled with deuterium at the C1-position. Calculations using the M06-2X functional with large basis sets indicate the tautomeric form of an estrogen-DNA adduct present when glycosidic bonds cleavage occurs is comprised of an aromatic A ring structure. This tautomeric form was further verified by use of deuterium labelling of the catechol precursor use to form the estrogen o-quinone. Regioselective deuterium labelling at the C1-position of the estrogen A ring allows discrimination between two tautomeric forms of a reaction intermediate either of which could be present during glycosidic bond cleavage. HPLC-MS analysis indicates a reactive intermediate with a m/z of 552.22 consistent with a tautomeric form containing no deuterium. This intermediate is consistent with a reaction mechanism that involves: (1) proton assisted Michael addition; (2) re-aromatization of the estrogen A ring; and (3) glycosidic bond cleavage to form the known estrogen-DNA adduct, 4-OHE1-1-N7Gua. View Full-Text
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Stack, D.E. Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate. Metabolites 2015, 5, 475-488.
Stack DE. Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate. Metabolites. 2015; 5(3):475-488.Chicago/Turabian Style
Stack, Douglas E. 2015. "Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate." Metabolites 5, no. 3: 475-488.