Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges

Valentina Sepe*, Claudio D'Amore, Raffella Ummarino, Barbara Renga, Maria Valeria D'Auria, Ettore Novellino, Annamaria Sinisi, Orazio Taglialatela-Scafati, Yoichi Nakao, Vittorio Limongelli, Angela Zampella, Stefano Fiorucci

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


Pregnane-X-receptor (PXR) is a member of nuclear receptors superfamily that activates gene transcription by binding to responsive elements in the promoter of target genes. PXR is a master gene orchestrating the expression/activity of genes involved in the metabolism of endobiotics including bilirubin, bile acids, glucose and lipid. In addition PXR oversights the metabolism of the large majority of xenobiotics including a large amount of prescribing drugs. Thus, developing PXR ligands represents a great opportunity for a therapeutic intervention on human diseases including diabetes, obesity, dyslipidemias and liver disorders. To this end, natural compounds represent an arsenal of new chemical scaffolds useful for the identification of novel PXR ligands. Here, we report a series of 4-methylenesteroid derivatives isolated from Theonella marine sponges as novel PXR modulators. In addition, combining medicinal chemistry, pharmacological experiments and computational studies, we have investigated the effects of different modifications on ring A and on the side chain of 4-methylenesteroid derivatives toward PXR modulation. This study provides the molecular bases of ligand/PXR interaction useful for designing novel PXR modulators.

Original languageEnglish
Pages (from-to)126-134
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2014 Feb 12


  • 4-Methylenesteroids
  • Conicasterol
  • Molecular docking
  • Pregnane-X-receptor
  • Structure-activity relationship
  • Theonella marine sponges

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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