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

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12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2448-2466
Number of pages19
JournalMarine Drugs
Volume10
Issue number11
DOIs
Publication statusPublished - 2012 Nov 1

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Keywords

  • Chemical modification
  • Farnesoid-X-receptor
  • Marine sponges
  • Nuclear receptors
  • Steroids
  • Structure-activity relationship
  • Theonella swinhoei
  • Theonellasterol

ASJC Scopus subject areas

  • Drug Discovery

Cite this

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