title: Marine and semi-synthetic hydroxysteroids as new scaffolds for pregnane X receptor modulation.
abstract: In recent years many sterols with unusual structures and promising biological profiles have been identified from marine sources. Here we report the isolation of a series of 24-alkylated-hydroxysteroids from the soft coral Sinularia kavarattiensis, acting as pregnane X receptor (PXR) modulators. Starting from this scaffold a number of derivatives were prepared and evaluated for their ability to activate the PXR by assessing transactivation and quantifying gene expression. Our study reveals that ergost-5-en-3β-ol (4) induces PXR transactivation in HepG2 cells and stimulates the expression of the PXR target gene CYP3A4. To shed light on the molecular basis of the interaction between these ligands and PXR, we investigated, through docking simulations, the binding mechanism of the most potent compound of the series, 4, to the PXR. Our findings provide useful functional and structural information to guide further investigations and drug design.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. valentina.sepe@unina.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. fr.dileva@gmail.com.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.affiliation: Department Experimental and Clinical Medicine, University of Perugia, Via Gambuli 1, S. Andrea delle Fratte, Perugia 06132, Italy. claudiodamore1983@gmail.com.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. carmen.festa@unina.it.
authors.forename: Carmen
authors.initials: C
authors.lastname: Festa
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. sidemari@unina.it.
authors.forename: Simona
authors.initials: S
authors.lastname: De Marino
authors.affiliation: Department Experimental and Clinical Medicine, University of Perugia, Via Gambuli 1, S. Andrea delle Fratte, Perugia 06132, Italy. barbara.renga@unipg.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. madauria@unina.it.
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. ettore.novellino@unina.it.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. vittoriolimongelli@gmail.com.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.affiliation: CSIR-National Institute of Oceanography, Dona Paula, Goa 403004, India. lisette@nio.org.
authors.forename: Lisette
authors.initials: L
authors.lastname: D'Souza
authors.affiliation: CSIR-National Institute of Oceanography, Dona Paula, Goa 403004, India. mmajik@nio.org.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Majik
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Napoli, Italy. angela.zampella@unina.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Department Experimental and Clinical Medicine, University of Perugia, Via Gambuli 1, S. Andrea delle Fratte, Perugia 06132, Italy. stefano.fiorucci@unipg.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D037421:Anthozoa / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006914:Hydroxysteroids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008024:Ligands; D062105:Molecular Docking Simulation; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism
chemical_list: D006914:Hydroxysteroids; D008024:Ligands; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A