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, Youichi Nakao, Nobuhiro Fusetani, Stefano Fiorucci, Angela Zampella

    Research output: Contribution to journalArticle

    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

    Fingerprint

    Theonella
    Porifera
    Structure-Activity Relationship
    Hydroxyl Radical
    Carbon
    Transcriptional Activation
    Hydrogen
    Pharmacology
    7-hydroxytheonellasterol

    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., ... 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

    Preliminary structure-activity relationship on theonellasterol, a new chemotype of FXR antagonist, from the marine sponge Theonella swinhoei. / Sepe, Valentina; Ummarino, Raffaella; D'Auria, Maria Valeria; Taglialatela-Scafati, Orazio; De Marino, Simona; D'Amore, Claudio; Renga, Barbara; Chini, Maria Giovanna; Bifulco, Giuseppe; Nakao, Youichi; Fusetani, Nobuhiro; Fiorucci, Stefano; Zampella, Angela.

    In: Marine Drugs, Vol. 10, No. 11, 11.2012, p. 2448-2466.

    Research output: Contribution to journalArticle

    Sepe, V, Ummarino, R, D'Auria, MV, Taglialatela-Scafati, O, De Marino, S, D'Amore, C, Renga, B, Chini, MG, 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, vol. 10, no. 11, pp. 2448-2466. https://doi.org/10.3390/md10112448
    Sepe, Valentina ; Ummarino, Raffaella ; D'Auria, Maria Valeria ; Taglialatela-Scafati, Orazio ; De Marino, Simona ; D'Amore, Claudio ; Renga, Barbara ; Chini, Maria Giovanna ; Bifulco, Giuseppe ; Nakao, Youichi ; Fusetani, Nobuhiro ; Fiorucci, Stefano ; Zampella, Angela. / Preliminary structure-activity relationship on theonellasterol, a new chemotype of FXR antagonist, from the marine sponge Theonella swinhoei. In: Marine Drugs. 2012 ; Vol. 10, No. 11. pp. 2448-2466.
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