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A Mechanistic Hypothesis for the Cytochrome P450-Catalyzed Cis-Trans Isomerization of 4-Hydroxytamoxifen: An Unusual Redox Reaction
Örebro Life Science Center, School of Science and Technology, Örebro University.
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2011 (English)In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 51, no 9, 2293-2301 p.Article 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, 2293-2301 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-105743DOI: 10.1021/ci2001082ISI: 000295114700026Scopus ID: 2-s2.0-80053302488OAI: oai:DiVA.org:kth-105743DiVA: diva2:571911
Note

QC 20121126

Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2012-11-26Bibliographically approved
In thesis
1. Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
Open this publication in new window or tab >>Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For decades tamoxifen (TAM) has been widely used for treatment of breast cancer by mediating mainly the estrogen receptor α (ERα) signaling pathways, whereby it suppresses estrogen stimulated cancer cell growth. The clinical response of TAM has been linked to cytochrome P450 2D6 (CYP2D6), which is the main isoform responsible for the conversion of TAM to the active metabolites 4-hydroxyTAM (OHT) and endoxifen. Numerous clinical studies have thus attempted to assess the effects of CYP2D6 genetic variants on patients treated by TAM. However, the studies have resulted in contradictive conclusions. This thesis focuses on computational investigations of TAM and its main target ERα. The results obtained describe how the ligands contact with the ERα ligand binding domain (LBD), and provide possible mechanisms responsible for the CYP2D6 activating in TAM treatment. In addition, the CYP-mediated biotransformation of TAM-like compounds is investigated. All studies in this thesis aim to a step towards developing improved therapeutic agents for breast cancer treatment. In paper I, molecular dynamics simulations of ligand-LBD complexes have been performed. The results indicate that although OHT is a high affinity metabolite, it may have more undesired estrogen-like properties than the parent drug TAM, as a consequence of the additional 4-hydroxy group. In papers II and V, quantum mechanics calculations have been performed to study how the ligands are bound to ERα LBD. It is found that different conformational isomers of TAM-like ligands are discriminated by the LBD. The interactions between ligands and His524-Leu525 in the LBD are correlated with the transcriptional activity of estrogen agonist compounds. In papers III and IV, different CYP-mediated biotransformations of TAM and derivatives are studied. Based on the results from the computations, we suggest two modified compounds which are highly possible to be activated by other CYP isoforms besides CYP2D6, thereby avoiding CYP2D6 genetic polymorphism. Overall, the results generally agree with the hitherto available experimental results. Further experimental studies are needed to verify the proposed principles of ligands signaling through ERα, and to test the suggested CYP-mediated reactions and the bioactivity of the modified compounds.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. vi, 58 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2012:23
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-105721 (URN)978-91-7501-586-6 (ISBN)
Public defence
2012-12-18, FB53, Albanova Universitetscentrum, Stockholm, 14:00 (English)
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Note

QC 20121126

Available from: 2012-11-26 Created: 2012-11-23 Last updated: 2012-11-26Bibliographically approved

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