Bazedoxifene-scaffold-based mimetics of solomonsterols A and B as novel pregnane X receptor antagonists

J Med Chem. 2014 Jun 12;57(11):4819-33. doi: 10.1021/jm500351m. Epub 2014 May 28.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catechols / chemical synthesis*
  • Catechols / chemistry
  • Catechols / pharmacology
  • Cholanes / chemistry*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors
  • Down-Regulation
  • Genes, Reporter
  • Hep G2 Cells
  • Humans
  • Hydrogen Bonding
  • Hydroquinones / chemical synthesis*
  • Hydroquinones / chemistry
  • Hydroquinones / pharmacology
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Luciferases / genetics
  • Models, Molecular
  • Molecular Mimicry
  • Pregnane X Receptor
  • Receptors, Steroid / agonists
  • Receptors, Steroid / antagonists & inhibitors*
  • Receptors, Steroid / metabolism
  • Structure-Activity Relationship
  • Sulfuric Acid Esters / chemistry*
  • Transcriptional Activation

Substances

  • 24-norcholan-2,3,24-tryl-2,3,23-sulfuric acid
  • 4-(5-(3-hydroxypropoxy)-3-methyl-1H-indol-2-yl)benzene-1,2-diol
  • 4-(5-hydroxy-3-methyl-1H-indol-2-yl)benzene-1,2-diol
  • Catechols
  • Cholanes
  • Cytochrome P-450 CYP3A Inhibitors
  • Hydroquinones
  • Indoles
  • Pregnane X Receptor
  • Receptors, Steroid
  • Sulfuric Acid Esters
  • cholan-2,3,24-tryl-2,3,24-trisulfate
  • Luciferases
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • bazedoxifene