Bazedoxifene-scaffold-based mimetics of solomonsterols A and B as novel pregnane X receptor antagonists.
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.
Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
Žiga
Ž
Hodnik
Lucija
L
Peterlin Mašič
Tihomir
T
Tomašić
Domen
D
Smodiš
Claudio
C
D'Amore
Stefano
S
Fiorucci
Danijel
D
Kikelj
D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002757:Cholanes / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D015536:Down-Regulation; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D006860:Hydrogen Bonding; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013463:Sulfuric Acid Esters / Q000737:chemistry*; D015533:Transcriptional Activation
C562251:24-norcholan-2,3,24-tryl-2,3,23-sulfuric acid; C000590789:4-(5-(3-hydroxypropoxy)-3-methyl-1H-indol-2-yl)benzene-1,2-diol; C000590788:4-(5-hydroxy-3-methyl-1H-indol-2-yl)benzene-1,2-diol; D002396:Catechols; D002757:Cholanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D006873:Hydroquinones; D007211:Indoles; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013463:Sulfuric Acid Esters; C561233:cholan-2,3,24-tryl-2,3,24-trisulfate; D008156:Luciferases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C447119:bazedoxifene