Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects
Source at https://doi.org/10.1016/j.ejmech.2018.06.034. Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as l...
Published in: | European Journal of Medicinal Chemistry |
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Online Access: | https://hdl.handle.net/10037/15305 https://doi.org/10.1016/j.ejmech.2018.06.034 |
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ftunivtroemsoe:oai:munin.uit.no:10037/15305 2023-05-15T14:27:59+02:00 Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects Sæther, Thomas Paulsen, Steinar M Tungen, Jørn Eivind Vik, Anders Aursnes, Marius Holen, Torgeir Hansen, Trond Vidar Nebb, Hilde Irene 2018-06-18 https://hdl.handle.net/10037/15305 https://doi.org/10.1016/j.ejmech.2018.06.034 eng eng Elsevier European Journal of 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// info:eu-repo/grantAgreement/RCN/FRINATEK/230470/Norway/DEVELOPMENT OF AN ENANTIOSELECTIVE ORGANOCATALYZED IODOLACTONIZATION REACTION// https://doi.org/10.1016/j.ejmech.2018.06.034 Sæther, T., Paulsen, S.M., Tungen, J.E., Vik, A., Aursnes, M., Holen, T. . Nebb, H.I. (2018). Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects. European Journal of Medicinal Chemistry, 155 , 736-753. https://doi.org/10.1016/j.ejmech.2018.06.034 FRIDAID 1593672 doi:10.1016/j.ejmech.2018.06.034 0223-5234 1768-3254 https://hdl.handle.net/10037/15305 openAccess VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Journal article Tidsskriftartikkel Peer reviewed 2018 ftunivtroemsoe https://doi.org/10.1016/j.ejmech.2018.06.034 2021-06-25T17:56:19Z Source at https://doi.org/10.1016/j.ejmech.2018.06.034. Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC50 values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines. Article in Journal/Newspaper Arctic University of Tromsø: Munin Open Research Archive European Journal of Medicinal Chemistry 155 736 753 |
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Open Polar |
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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 |
spellingShingle |
VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 Sæther, Thomas Paulsen, Steinar M Tungen, Jørn Eivind Vik, Anders Aursnes, Marius Holen, Torgeir Hansen, Trond Vidar Nebb, Hilde Irene Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects |
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 |
description |
Source at https://doi.org/10.1016/j.ejmech.2018.06.034. Obesity and associated disorders such as metabolic syndrome and type 2 diabetes (T2D) have reached epidemic proportions. Several natural products have been reported as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, functioning as lead compounds towards developing new anti-diabetic drugs due to adverse side effects of existing PPAR drugs. We recently isolated and identified (7E)-9-oxohexadec-7-enoic acid (1) and (10E)-9-oxohexadec-10-enoic acid (2) from the marine algae Chaetoceros karianus. Herein we report the total synthesis, pharmacological characterization, and biological evaluations of these naturally occurring oxo-fatty acids (oFAs). The syntheses of 1 and 2 afforded sufficient material for extensive biological evaluations. Both oFAs show an appreciable dose-dependent activation of PPARα and -γ, with EC50 values in the micromolar range, and an ability to regulate important PPAR target genes in hepatocytes and adipocytes. Moreover, both 1 and 2 are able to drive adipogenesis when evaluated in the Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell model, but with lowered expression of adipocyte markers and reduced lipid accumulation compared to the drug rosiglitazone. This seems to be caused by a transient upregulation of PPARγ and C/EBPα expression. Importantly, whole transcriptome analysis shows that both compounds induce anti-diabetic gene programs in adipocytes by upregulating insulin-sensitizing adipokines and repressing pro-inflammatory cytokines. |
format |
Article in Journal/Newspaper |
author |
Sæther, Thomas Paulsen, Steinar M Tungen, Jørn Eivind Vik, Anders Aursnes, Marius Holen, Torgeir Hansen, Trond Vidar Nebb, Hilde Irene |
author_facet |
Sæther, Thomas Paulsen, Steinar M Tungen, Jørn Eivind Vik, Anders Aursnes, Marius Holen, Torgeir Hansen, Trond Vidar Nebb, Hilde Irene |
author_sort |
Sæther, Thomas |
title |
Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects |
title_short |
Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects |
title_full |
Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects |
title_fullStr |
Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects |
title_full_unstemmed |
Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects |
title_sort |
synthesis and biological evaluations of marine oxohexadecenoic acids: pparα/γ dual agonism and anti-diabetic target gene effects |
publisher |
Elsevier |
publishDate |
2018 |
url |
https://hdl.handle.net/10037/15305 https://doi.org/10.1016/j.ejmech.2018.06.034 |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
European Journal of 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// info:eu-repo/grantAgreement/RCN/FRINATEK/230470/Norway/DEVELOPMENT OF AN ENANTIOSELECTIVE ORGANOCATALYZED IODOLACTONIZATION REACTION// https://doi.org/10.1016/j.ejmech.2018.06.034 Sæther, T., Paulsen, S.M., Tungen, J.E., Vik, A., Aursnes, M., Holen, T. . Nebb, H.I. (2018). Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects. European Journal of Medicinal Chemistry, 155 , 736-753. https://doi.org/10.1016/j.ejmech.2018.06.034 FRIDAID 1593672 doi:10.1016/j.ejmech.2018.06.034 0223-5234 1768-3254 https://hdl.handle.net/10037/15305 |
op_rights |
openAccess |
op_doi |
https://doi.org/10.1016/j.ejmech.2018.06.034 |
container_title |
European Journal of Medicinal Chemistry |
container_volume |
155 |
container_start_page |
736 |
op_container_end_page |
753 |
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1766302091444224000 |