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A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen: an unusual redox reaction
Örebro University, School of Science and Technology.
Örebro University, School of Science and Technology.
Örebro University, School of Health and Medical Sciences.
Örebro University, School of Health and Medical Sciences.
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2011 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 9, p. 2293-2301Article in journal (Refereed) Published
Abstract [en]

We provide a detailed description of the cis-trans isomerization of 4-hydroxytamoxifen/endoxifen catalyzed by several isoforms from the cytochrome P450 (CYP) superfamily, including CYP1B1, CYP2B6, and CYP2C19. We show that the reactions mainly involve redox processes catalyzed by CYP, DFT calculation results strongly suggest that the isomerization occurs via a cationic intermediate. The cationic cis-isomer is more than 3 kcal/mol more stable than the trans form, resulting in an easier conversion from trans-to-cis than cis-to-trans. The cis-trans isomerization is a rarely reported CYP reaction and is ascribed to the lack of a second abstractable proton on the ethenyl group of the triarylvinyl class of substrates. The cationic intermediates thus formed instead of the stable dehydrogenation products allow for isomerization to occur. As a comparison, the reactions for the tamoxifen derivatives are compared to those of other substrates, 4-hydroxyacetanilide and raloxifene, for which the stable dehydrogenation products are formed.

Place, publisher, year, edition, pages
2011. Vol. 51, no 9, p. 2293-2301
National Category
Chemical Sciences Biomedical Laboratory Science/Technology
Research subject
Chemistry; Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-20857DOI: 10.1021/ci2001082ISI: 000295114700026OAI: oai:DiVA.org:oru-20857DiVA, id: diva2:476128
Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2018-02-14Bibliographically approved

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Gao, LiTu, YaoquanWegman [Palmebäck-Wegman], PiaWingren, Sten

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