Presentation Title

NMR analysis of the estrogen o-quinone to estrogen o-quinone methide equilibrium

Advisor Information

Douglas Stack

Location

Dr. C.C. and Mabel L. Criss Library

Presentation Type

Poster

Start Date

4-3-2016 2:30 PM

End Date

4-3-2016 4:00 PM

Abstract

Abstract: Electrophilic metabolites of estrogen, namely estrogen o-quinones, are genotoxic and have been associated with breast and other human cancers. The formation of estrogen o-quinones from catechol estrogens can also lead to o-quinone methides via tautomerization. This project aims to characterize the kinetic and thermodynamic properties of this o-quinone to o-quinone methide rearrangement. The o-quinone methide of 2-hydroxycatechol estrogens has been measured by trapping this reactive electrophile with various nucleophiles. Direct spectrophotometric observations, specifically NMR have not been reported. We have produced the estrogen o-quinones in deuterated acetonitrile to determine the stability of the o-quinones and detect any evidence of equilibration to the o-quinone methide. When estrogen-2,3-quinone is produced from 2-OHE1 in acetonitrile, the only tautomer observed in proton NMR is the o-quinone. No indication of o-quinone methide tautomer was detected. There is little change in the proton NMR spectra after several days at room temperature in acetonitrile. High level density functional calculations show the quinone methides to be more stable than their respective quinones. While more stable than the o-quinone, the o-quinone methide has a low lying LUMO that makes it reactive to even moderate nucleophiles. Attempts to facilitate the tautomerization with DBU, resulted in the disappearance of the o-quinone without subsequent appearance of the o-quinone methide. Acid catalysis with trifluoroacetic acid also did not produce equilibrium to o-quinone methide; however, the o-quinone did not rapidly decompose but was stable for days in this medium. A similar stability was observed for the 3,4-quinone. Molecular modelling NMR predictions were also generated.

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Mar 4th, 2:30 PM Mar 4th, 4:00 PM

NMR analysis of the estrogen o-quinone to estrogen o-quinone methide equilibrium

Dr. C.C. and Mabel L. Criss Library

Abstract: Electrophilic metabolites of estrogen, namely estrogen o-quinones, are genotoxic and have been associated with breast and other human cancers. The formation of estrogen o-quinones from catechol estrogens can also lead to o-quinone methides via tautomerization. This project aims to characterize the kinetic and thermodynamic properties of this o-quinone to o-quinone methide rearrangement. The o-quinone methide of 2-hydroxycatechol estrogens has been measured by trapping this reactive electrophile with various nucleophiles. Direct spectrophotometric observations, specifically NMR have not been reported. We have produced the estrogen o-quinones in deuterated acetonitrile to determine the stability of the o-quinones and detect any evidence of equilibration to the o-quinone methide. When estrogen-2,3-quinone is produced from 2-OHE1 in acetonitrile, the only tautomer observed in proton NMR is the o-quinone. No indication of o-quinone methide tautomer was detected. There is little change in the proton NMR spectra after several days at room temperature in acetonitrile. High level density functional calculations show the quinone methides to be more stable than their respective quinones. While more stable than the o-quinone, the o-quinone methide has a low lying LUMO that makes it reactive to even moderate nucleophiles. Attempts to facilitate the tautomerization with DBU, resulted in the disappearance of the o-quinone without subsequent appearance of the o-quinone methide. Acid catalysis with trifluoroacetic acid also did not produce equilibrium to o-quinone methide; however, the o-quinone did not rapidly decompose but was stable for days in this medium. A similar stability was observed for the 3,4-quinone. Molecular modelling NMR predictions were also generated.