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Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei

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-...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509528/
https://www.ncbi.nlm.nih.gov/pubmed/23203270
http://dx.doi.org/10.3390/md10112448
Descripción
Sumario: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.