Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist
Source at https://doi.org/10.1016/j.bmc.2019.07.032. The peroxisome proliferator activated receptors (PPARs) are important drug targets in treatment of metabolic and inflammatory disorders. Fibrates, acting as PPARα agonists, have been widely used lipid-lowering agents for decades. However, the curr...
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ftunivtroemsoe:oai:munin.uit.no:10037/16078 2023-05-15T14:27:45+02:00 Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist Arnesen, Henriette Haj-Yasein, Nadia N. Tungen, Jørn E. Soedling, Helen Matthews, Jason Paulsen, Steinar M. Nebb, Hilde I. Sylte, Ingebrigt Hansen, Trond Vidar Sæther, Thomas 2019-07-19 https://hdl.handle.net/10037/16078 https://doi.org/10.1016/j.bmc.2019.07.032 eng eng Elsevier Bioorganic & Medicinal Chemistry info:eu-repo/grantAgreement/RCN/BIOTEK2021/208452/Norway/Nuclear receptor ligands from Arctic marine organisms; Bioprospecting, structure, synthesis and evaluation as drug to treat metabolic syndro// Arnesen, H., Haj-Yasein, N.N., Tungen, J.T., Soedling, H., Matthews, J., Paulsen, S.M. . Sæther, T. (2019). Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist. Bioorganic & Medicinal Chemistry, 27 (18), 4059-4068. https://doi.org/10.1016/j.bmc.2019.07.032 FRIDAID 1718462 doi:10.1016/j.bmc.2019.07.032 0968-0896 1464-3391 https://hdl.handle.net/10037/16078 openAccess VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Peroxisome proliferator activated receptor Agonist Oxohexadecenoic acid Isoxazole Lipid-lowering Microalgae Chaetoceros karianus Journal article Tidsskriftartikkel Peer reviewed 2019 ftunivtroemsoe https://doi.org/10.1016/j.bmc.2019.07.032 2021-06-25T17:56:47Z Source at https://doi.org/10.1016/j.bmc.2019.07.032. The peroxisome proliferator activated receptors (PPARs) are important drug targets in treatment of metabolic and inflammatory disorders. Fibrates, acting as PPARα agonists, have been widely used lipid-lowering agents for decades. However, the currently available PPARα targeting agents show low subtype-specificity and consequently a search for more potent agonists have emerged. In this study, previously isolated oxohexadecenoic acids from the marine algae Chaetoceros karianus were used to design a PPARα-specific analogue. Herein we report the design, synthesis, molecular modelling studies and biological evaluations of the novel 3,5-disubstituted isoxazole analogue 6-(5-heptyl-1,2-oxazol-3-yl)hexanoic acid ( 1 ), named ADAM. ADAM shows a clear receptor preference and significant dose-dependent activation of PPARα (EC 50 = 47 µM) through its ligand-binding domain (LBD). Moreover, ADAM induces expression of important PPARα target genes, such as CPT1A , in the Huh7 cell line and primary mouse hepatocytes. In addition, ADAM exhibits a moderate ability to regulate PPARγ target genes and drive adipogenesis. Molecular modelling studies indicated that ADAM docks its carboxyl group into opposite ends of the PPARα and -γ LBD. ADAM interacts with the receptor-activating polar network of amino acids (Tyr501, His447 and Ser317) in PPARα, but not in PPARγ LBD. This may explain the lack of PPARγ agonism, and argues for a PPARα-dependent adipogenic function. Such compounds are of interest towards developing new lipid-lowering remedies. Article in Journal/Newspaper Arctic University of Tromsø: Munin Open Research Archive Bioorganic & Medicinal Chemistry 27 18 4059 4068 |
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University of Tromsø: Munin Open Research Archive |
op_collection_id |
ftunivtroemsoe |
language |
English |
topic |
VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Peroxisome proliferator activated receptor Agonist Oxohexadecenoic acid Isoxazole Lipid-lowering Microalgae Chaetoceros karianus |
spellingShingle |
VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Peroxisome proliferator activated receptor Agonist Oxohexadecenoic acid Isoxazole Lipid-lowering Microalgae Chaetoceros karianus Arnesen, Henriette Haj-Yasein, Nadia N. Tungen, Jørn E. Soedling, Helen Matthews, Jason Paulsen, Steinar M. Nebb, Hilde I. Sylte, Ingebrigt Hansen, Trond Vidar Sæther, Thomas Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist |
topic_facet |
VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Peroxisome proliferator activated receptor Agonist Oxohexadecenoic acid Isoxazole Lipid-lowering Microalgae Chaetoceros karianus |
description |
Source at https://doi.org/10.1016/j.bmc.2019.07.032. The peroxisome proliferator activated receptors (PPARs) are important drug targets in treatment of metabolic and inflammatory disorders. Fibrates, acting as PPARα agonists, have been widely used lipid-lowering agents for decades. However, the currently available PPARα targeting agents show low subtype-specificity and consequently a search for more potent agonists have emerged. In this study, previously isolated oxohexadecenoic acids from the marine algae Chaetoceros karianus were used to design a PPARα-specific analogue. Herein we report the design, synthesis, molecular modelling studies and biological evaluations of the novel 3,5-disubstituted isoxazole analogue 6-(5-heptyl-1,2-oxazol-3-yl)hexanoic acid ( 1 ), named ADAM. ADAM shows a clear receptor preference and significant dose-dependent activation of PPARα (EC 50 = 47 µM) through its ligand-binding domain (LBD). Moreover, ADAM induces expression of important PPARα target genes, such as CPT1A , in the Huh7 cell line and primary mouse hepatocytes. In addition, ADAM exhibits a moderate ability to regulate PPARγ target genes and drive adipogenesis. Molecular modelling studies indicated that ADAM docks its carboxyl group into opposite ends of the PPARα and -γ LBD. ADAM interacts with the receptor-activating polar network of amino acids (Tyr501, His447 and Ser317) in PPARα, but not in PPARγ LBD. This may explain the lack of PPARγ agonism, and argues for a PPARα-dependent adipogenic function. Such compounds are of interest towards developing new lipid-lowering remedies. |
format |
Article in Journal/Newspaper |
author |
Arnesen, Henriette Haj-Yasein, Nadia N. Tungen, Jørn E. Soedling, Helen Matthews, Jason Paulsen, Steinar M. Nebb, Hilde I. Sylte, Ingebrigt Hansen, Trond Vidar Sæther, Thomas |
author_facet |
Arnesen, Henriette Haj-Yasein, Nadia N. Tungen, Jørn E. Soedling, Helen Matthews, Jason Paulsen, Steinar M. Nebb, Hilde I. Sylte, Ingebrigt Hansen, Trond Vidar Sæther, Thomas |
author_sort |
Arnesen, Henriette |
title |
Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist |
title_short |
Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist |
title_full |
Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist |
title_fullStr |
Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist |
title_full_unstemmed |
Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist |
title_sort |
molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a pparα-selective agonist |
publisher |
Elsevier |
publishDate |
2019 |
url |
https://hdl.handle.net/10037/16078 https://doi.org/10.1016/j.bmc.2019.07.032 |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
Bioorganic & Medicinal Chemistry info:eu-repo/grantAgreement/RCN/BIOTEK2021/208452/Norway/Nuclear receptor ligands from Arctic marine organisms; Bioprospecting, structure, synthesis and evaluation as drug to treat metabolic syndro// Arnesen, H., Haj-Yasein, N.N., Tungen, J.T., Soedling, H., Matthews, J., Paulsen, S.M. . Sæther, T. (2019). Molecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonist. Bioorganic & Medicinal Chemistry, 27 (18), 4059-4068. https://doi.org/10.1016/j.bmc.2019.07.032 FRIDAID 1718462 doi:10.1016/j.bmc.2019.07.032 0968-0896 1464-3391 https://hdl.handle.net/10037/16078 |
op_rights |
openAccess |
op_doi |
https://doi.org/10.1016/j.bmc.2019.07.032 |
container_title |
Bioorganic & Medicinal Chemistry |
container_volume |
27 |
container_issue |
18 |
container_start_page |
4059 |
op_container_end_page |
4068 |
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1766301653373288448 |