title: Preliminary structure-activity relationship on theonellasterol, a new chemotype of FXR antagonist, from the marine sponge Theonella swinhoei.
abstract: Using theonellasterol as a novel FXR antagonist hit, we prepared a series of semi-synthetic derivatives in order to gain insight into the structural requirements for exhibiting antagonistic activity. These derivatives are characterized by modification at the exocyclic carbon-carbon double bond at C-4 and at the hydroxyl group at C-3 and were prepared from theonellasterol using simple reactions. Pharmacological investigation showed that the introduction of a hydroxyl group at C-4 as well as the oxidation at C-3 with or without concomitant modification at the exomethylene functionality preserve the ability of theonellasterol to inhibit FXR transactivation caused by CDCA. Docking analysis showed that the placement of these molecules in the FXR-LBD is well stabilized when on ring A functional groups, able to form hydrogen bonds and π interactions, are present.
authors.affiliation: Department of Chemistry of Natural Products, University of Naples "Federico II", Via D. Montesano 49, 80131 Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ummarino
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.forename: Simona De
authors.initials: SD
authors.lastname: Marino
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakao
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fusetani
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D056945:Hep G2 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013261:Sterols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D047232:Theonella / Q000737:chemistry*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D013261:Sterols; D000099150:Receptor, Farnesoid X-Activated; C412852:7-hydroxytheonellasterol