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Magnolol dimer-derived fragments as PPARγ-selective probes
Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent struc...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180429/ https://www.ncbi.nlm.nih.gov/pubmed/30232493 http://dx.doi.org/10.1039/c8ob01745j |
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author | Dreier, Dominik Resetar, Mirta Temml, Veronika Rycek, Lukas Kratena, Nicolas Schnürch, Michael Schuster, Daniela Dirsch, Verena M. Mihovilovic, Marko D. |
author_facet | Dreier, Dominik Resetar, Mirta Temml, Veronika Rycek, Lukas Kratena, Nicolas Schnürch, Michael Schuster, Daniela Dirsch, Verena M. Mihovilovic, Marko D. |
author_sort | Dreier, Dominik |
collection | PubMed |
description | Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand–target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist. |
format | Online Article Text |
id | pubmed-6180429 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-61804292018-10-12 Magnolol dimer-derived fragments as PPARγ-selective probes Dreier, Dominik Resetar, Mirta Temml, Veronika Rycek, Lukas Kratena, Nicolas Schnürch, Michael Schuster, Daniela Dirsch, Verena M. Mihovilovic, Marko D. Org Biomol Chem Chemistry Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand–target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist. Royal Society of Chemistry 2018-10-07 2018-09-20 /pmc/articles/PMC6180429/ /pubmed/30232493 http://dx.doi.org/10.1039/c8ob01745j Text en This journal is © The Royal Society of Chemistry 2018 http://creativecommons.org/licenses/by/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) |
spellingShingle | Chemistry Dreier, Dominik Resetar, Mirta Temml, Veronika Rycek, Lukas Kratena, Nicolas Schnürch, Michael Schuster, Daniela Dirsch, Verena M. Mihovilovic, Marko D. Magnolol dimer-derived fragments as PPARγ-selective probes |
title | Magnolol dimer-derived fragments as PPARγ-selective probes
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title_full | Magnolol dimer-derived fragments as PPARγ-selective probes
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title_fullStr | Magnolol dimer-derived fragments as PPARγ-selective probes
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title_full_unstemmed | Magnolol dimer-derived fragments as PPARγ-selective probes
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title_short | Magnolol dimer-derived fragments as PPARγ-selective probes
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title_sort | magnolol dimer-derived fragments as pparγ-selective probes |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180429/ https://www.ncbi.nlm.nih.gov/pubmed/30232493 http://dx.doi.org/10.1039/c8ob01745j |
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