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Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei
Department of Chemistry of Natural Products, University of Naples “Federico II”, via D. Montesano 49, 80131 Naples, Italy
Department of Clinical and Experimental Medicine Clinica e Sperimentale, University of Perugia, Nuova Facolta di Medicina e Chirurgia, via Gerardo Dottori 1, S. Andrea delle Fratte, 06132 Perugia, Italy
Department of Pharmaceutical and Biomedical Sciences, University of Salerno, via Ponte don Melillo, 84084 Fisciano (SA), Italy
Department of Chemistry and Biochemistry, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo, 169-8555, Japan
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 31 July 2012; in revised form: 28 August 2012 / Accepted: 24 October 2012 / Published: 5 November 2012
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.
Keywords: marine sponges; Theonella swinhoei; steroids; theonellasterol; nuclear receptors; farnesoid-X-receptor; chemical modification; structure-activity relationship
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Sepe, V.; Ummarino, R.; D'Auria, M.V.; Taglialatela-Scafati, O.; Marino, S.D.; D'Amore, C.; Renga, B.; Chini, M.G.; Bifulco, G.; Nakao, Y.; Fusetani, N.; Fiorucci, S.; Zampella, A. Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei. Mar. Drugs 2012, 10, 2448-2466.
Sepe V, Ummarino R, D'Auria MV, Taglialatela-Scafati O, Marino SD, D'Amore C, Renga B, Chini MG, Bifulco G, Nakao Y, Fusetani N, Fiorucci S, Zampella A. Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei. Marine Drugs. 2012; 10(11):2448-2466.
Sepe, Valentina; Ummarino, Raffaella; D'Auria, Maria V.; Taglialatela-Scafati, Orazio; Marino, Simona D.; D'Amore, Claudio; Renga, Barbara; Chini, Maria G.; Bifulco, Giuseppe; Nakao, Yoichi; Fusetani, Nobuhiro; Fiorucci, Stefano; Zampella, Angela. 2012. "Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei." Mar. Drugs 10, no. 11: 2448-2466.