CYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues

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dc.contributor.authorRuparelia, K. C.
dc.contributor.authorZeka, K.
dc.contributor.authorBeresford, Kenneth J. M.
dc.contributor.authorWilsher, Nicola E.
dc.contributor.authorPotter, Gerard A.
dc.contributor.authorAndroutsopoulos, V. P.
dc.contributor.authorBrucoli, Federico
dc.contributor.authorArroo, R. R. J.
dc.date.acceptance2024-01-02
dc.date.accessioned2024-01-15T16:37:24Z
dc.date.available2024-01-15T16:37:24Z
dc.date.issued2024-01-15
dc.descriptionopen access article
dc.description.abstractNaturally occurring stilbenoids, such as the (E)-stilbenoid resveratrol and the (Z)-stilbenoid combretastatin A4, have been considered as promising lead compounds for the development of anticancer drugs. The antitumour properties of stilbenoids are known to be modulated by cytochrome P450 enzymes CYP1A1 and CYP1B1, which contribute to extrahepatic phase I xenobiotic and drug metabolism. Thirty-four methyl ether analogues of resveratrol were synthesised, and their anticancer properties were assessed, using the MTT cell proliferation assay on a panel of human breast cell lines. Breast tumour cell lines that express CYP1 were significantly more strongly affected by the resveratrol analogues than the cell lines that did not have CYP1 activity. Metabolism studies using isolated CYP1 enzymes provided further evidence that (E)-stilbenoids can be substrates for these enzymes. Structures of metabolic products were confirmed by comparison with synthetic standards and LC-MS co-elution studies. The most promising stilbenoid was (E)-4,3′,4′,5′-tetramethoxystilbene (DMU212). The compound itself showed low to moderate cytotoxicity, but upon CYP1-catalysed dealkylation, some highly cytotoxic metabolites were formed. Thus, DMU212 selectively affects proliferation of cells that express CYP1 enzymes.
dc.funderNo external funder
dc.identifier.citationRuparelia, K.C., Zeka, K., Beresford, K.J.M., Wilsher, N.E., Potter, G.A., Androutsopoulos, V.P., Brucoli, F., Arroo, R.R.J. (2024) CYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues. Molecules, 29 (2), 423
dc.identifier.doihttps://doi.org/10.3390/molecules29020423
dc.identifier.issn1420-3049
dc.identifier.urihttps://hdl.handle.net/2086/23467
dc.language.isoen
dc.peerreviewedYes
dc.publisherMDPI
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)
dc.rightsAttribution 2.0 UK: England & Walesen
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/
dc.subjectStilbenes
dc.subjectCYP1A1
dc.subjectCYP1B1
dc.subjectProdrug
dc.subjectWittig reaction
dc.subjectBreast cancer
dc.titleCYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues
dc.typeArticle

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