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

Marine Drugs

Valentina Sepe¹  Raffaella Ummarino¹  Maria Valeria D𠆚uria¹  Orazio Taglialatela-Scafati¹  Simona De Marino¹  Claudio D𠆚more⁴  Barbara Renga⁴  Maria Giovanna Chini³  Giuseppe Bifulco³  Yoichi Nakao²  Nobuhiro Fusetani²  Stefano Fiorucci⁴ 

[1] Department of Chemistry of Natural Products, University of Naples “Federico II”, via D. Montesano 49, 80131 Naples, Italy;Department of Chemistry and Biochemistry, Waseda University, 3-4-1 Okubo, Shinjuku-ku, Tokyo, 169-8555, Japan;Department of Pharmaceutical and Biomedical Sciences, University of Salerno, via Ponte don Melillo, 84084 Fisciano (SA), 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;

关键词: marine sponges;    Theonella swinhoei;    steroids;    theonellasterol;    nuclear receptors;    farnesoid-X-receptor;    chemical modification;    structure-activity relationship;   

DOI  :  10.3390/md10112448

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.