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Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei
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-...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509528/ https://www.ncbi.nlm.nih.gov/pubmed/23203270 http://dx.doi.org/10.3390/md10112448 |
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author | Sepe, Valentina Ummarino, Raffaella D’Auria, Maria Valeria Taglialatela-Scafati, Orazio Marino, Simona De D’Amore, Claudio Renga, Barbara Chini, Maria Giovanna Bifulco, Giuseppe Nakao, Yoichi Fusetani, Nobuhiro Fiorucci, Stefano Zampella, Angela |
author_facet | Sepe, Valentina Ummarino, Raffaella D’Auria, Maria Valeria Taglialatela-Scafati, Orazio Marino, Simona De D’Amore, Claudio Renga, Barbara Chini, Maria Giovanna Bifulco, Giuseppe Nakao, Yoichi Fusetani, Nobuhiro Fiorucci, Stefano Zampella, Angela |
author_sort | Sepe, Valentina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3509528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-35095282012-12-10 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 Marino, Simona De D’Amore, Claudio Renga, Barbara Chini, Maria Giovanna Bifulco, Giuseppe Nakao, Yoichi Fusetani, Nobuhiro Fiorucci, Stefano Zampella, Angela Mar Drugs Article 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. MDPI 2012-11-05 /pmc/articles/PMC3509528/ /pubmed/23203270 http://dx.doi.org/10.3390/md10112448 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Sepe, Valentina Ummarino, Raffaella D’Auria, Maria Valeria Taglialatela-Scafati, Orazio Marino, Simona De D’Amore, Claudio Renga, Barbara Chini, Maria Giovanna Bifulco, Giuseppe Nakao, Yoichi Fusetani, Nobuhiro Fiorucci, Stefano Zampella, Angela Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei |
title | Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei |
title_full | Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei |
title_fullStr | Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei |
title_full_unstemmed | Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei |
title_short | Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei |
title_sort | preliminary structure-activity relationship on theonellasterol, a new chemotype of fxr antagonist, from the marine sponge theonella swinhoei |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509528/ https://www.ncbi.nlm.nih.gov/pubmed/23203270 http://dx.doi.org/10.3390/md10112448 |
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