Abstract
Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug-metabolizing enzymes and transporters. The overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multidrug resistance in anticancer treatments. We describe the discovery of novel bazedoxifene-scaffold-based PXR antagonists inspired by the marine sulfated steroids solomonsterol A and B as natural leads. A luciferase reporter assay on a PXR-transfected HepG2 cell line identified compounds 19-24 as promising PXR antagonists. Further structure-activity relationship studies of the most active PXR antagonist from the series (compound 20, IC50 = 11 μM) revealed the importance of hydroxyl groups as hydrogen-bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC50 = 14 μM), in addition to the downregulation of PXR expression, exhibited inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase-I drug metabolism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Catechols / chemical synthesis*
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Catechols / chemistry
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Catechols / pharmacology
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Cholanes / chemistry*
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors
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Down-Regulation
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Genes, Reporter
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Hep G2 Cells
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Humans
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Hydrogen Bonding
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Hydroquinones / chemical synthesis*
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Hydroquinones / chemistry
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Hydroquinones / pharmacology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Luciferases / genetics
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Models, Molecular
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Molecular Mimicry
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Pregnane X Receptor
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Receptors, Steroid / agonists
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Receptors, Steroid / antagonists & inhibitors*
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Receptors, Steroid / metabolism
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Structure-Activity Relationship
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Sulfuric Acid Esters / chemistry*
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Transcriptional Activation
Substances
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24-norcholan-2,3,24-tryl-2,3,23-sulfuric acid
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4-(5-(3-hydroxypropoxy)-3-methyl-1H-indol-2-yl)benzene-1,2-diol
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4-(5-hydroxy-3-methyl-1H-indol-2-yl)benzene-1,2-diol
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Catechols
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Cholanes
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Cytochrome P-450 CYP3A Inhibitors
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Hydroquinones
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Indoles
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Pregnane X Receptor
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Receptors, Steroid
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Sulfuric Acid Esters
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cholan-2,3,24-tryl-2,3,24-trisulfate
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Luciferases
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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bazedoxifene