Preliminary structure-activity relationship on theonellasterol, a new chemotype of FXR antagonist, from the marine sponge Theonella swinhoei

• Published in: Marine drugs Vol. 10; no. 11; pp. 2448 - 2466
• Main Authors: Sepe, Valentina, Ummarino, Raffaella, D'Auria, Maria Valeria, Taglialatela-Scafati, Orazio, Marino, Simona De, D'Amore, Claudio, Renga, Barbara, Chini, Maria Giovanna, Bifulco, Giuseppe, Nakao, Yoichi, Fusetani, Nobuhiro, Fiorucci, Stefano, Zampella, Angela
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05-11-2012; MDPI
• Subjects: Animals; chemical modification; farnesoid-X-receptor; Hep G2 Cells; Humans; Marine; marine sponges; Molecular Docking Simulation; nuclear receptors; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; steroids; Sterols - chemical synthesis; Sterols - chemistry; Sterols - pharmacology; Structure-Activity Relationship; Theonella - chemistry; Theonella swinhoei; theonellasterol
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md10112448

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.