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

Valentina Sepe, Raffaella Ummarino, Maria Valeria D'Auria, Orazio Taglialatela-Scafati, Simona De Marino, Claudio D'Amore, Barbara Renga, Maria Giovanna Chini, Giuseppe Bifulco, Yoichi Nakao, Nobuhiro Fusetani, Stefano Fiorucci, Angela Zampella

研究成果: Article

12 引用 (Scopus)

抜粋

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.

元の言語English
ページ(範囲)2448-2466
ページ数19
ジャーナルMarine Drugs
10
発行部数11
DOI
出版物ステータスPublished - 2012 11

ASJC Scopus subject areas

  • Drug Discovery

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    Sepe, V., Ummarino, R., D'Auria, M. V., Taglialatela-Scafati, O., De Marino, S., D'Amore, C., Renga, B., Chini, M. G., Bifulco, G., Nakao, Y., Fusetani, N., Fiorucci, S., & Zampella, A. (2012). Preliminary structure-activity relationship on theonellasterol, a new chemotype of FXR antagonist, from the marine sponge Theonella swinhoei. Marine Drugs, 10(11), 2448-2466. https://doi.org/10.3390/md10112448