Cargando…

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-...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2012
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
_version_ 1782251348262125568
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
work_keys_str_mv AT sepevalentina preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT ummarinoraffaella preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT dauriamariavaleria preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT taglialatelascafatiorazio preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT marinosimonade preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT damoreclaudio preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT rengabarbara preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT chinimariagiovanna preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT bifulcogiuseppe preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT nakaoyoichi preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT fusetaninobuhiro preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT fioruccistefano preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei
AT zampellaangela preliminarystructureactivityrelationshipontheonellasterolanewchemotypeoffxrantagonistfromthemarinespongetheonellaswinhoei