title: Insights on pregnane-X-receptor modulation. Natural and semisynthetic steroids from Theonella marine sponges.
abstract: 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.
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy. Electronic address: valentina.sepe@unina.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, 06132 Perugia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Raffella
authors.initials: R
authors.lastname: Ummarino
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, 06132 Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Sinisi
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.affiliation: Department of Chemistry and Biochemistry, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakao
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", 80131 Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, 06132 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D001665:Binding Sites; D001688:Biological Products / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D000077297:Pregnane X Receptor; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D047232:Theonella / Q000737:chemistry*; D014166:Transferases
chemical_list: D001688:Biological Products; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013256:Steroids; D014166:Transferases
keywords: 4-Methylenesteroids; Conicasterol; Molecular docking; Pregnane-X-receptor; Structure–activity relationship; Theonella marine sponges