title: Theonellasterols and conicasterols from Theonella swinhoei. Novel marine natural ligands for human nuclear receptors.
abstract: Silica gel column chromatography, followed by HPLC purification on the apolar fraction of the methanol extract of marine sponge Theonella swinhoei, resulted in the isolation of a library of 10 polyhydroxylated steroids which we named theonellasterols B-H (1-7) and conicasterols B-D (8-10). The structures were determined on the basis of extensive spectroscopic data (MS, (1)H and (13)C NMR, COSY, HSQC, HMBC, and ROESY) analysis, and the putative binding mode to nuclear receptors (NRs) has been obtained through docking calculations. Pharmacological and structure-activity relationship analysis demonstrate that these natural polyhydroxylated steroids are potent ligands of human nuclear pregnane receptor (PXR) and modulator of farnesoid-X-receptor (FXR). In addition, the molecular characterization of theonellasterol G allowed the identification of the first FXR modulator and PXR ligand so far identified. Exposure of liver cells to this agent resulted in potent induction of PXR-regulated genes and modulation of FXR-regulated genes, highlighting its pharmacological potential in the treatment of liver disorders.
authors.affiliation: Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: De Marino
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ummarino
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Cécile
authors.initials: C
authors.lastname: Debitus
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008386:Marine Biology; D008958:Models, Molecular; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization; D013261:Sterols / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D047232:Theonella / Q000737:chemistry*
chemical_list: D008024:Ligands; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013261:Sterols