Show simple item record

dc.contributor.authorArnesen, Henriette
dc.contributor.authorHaj-Yasein, Nadia N.
dc.contributor.authorTungen, Jørn E.
dc.contributor.authorSoedling, Helen
dc.contributor.authorMatthews, Jason
dc.contributor.authorPaulsen, Steinar M.
dc.contributor.authorNebb, Hilde I.
dc.contributor.authorSylte, Ingebrigt
dc.contributor.authorHansen, Trond Vidar
dc.contributor.authorSæther, Thomas
dc.date.accessioned2019-09-03T10:36:47Z
dc.date.available2019-09-03T10:36:47Z
dc.date.issued2019-07-19
dc.description.abstractThe 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 <i>Chaetoceros karianus</i> 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 (<b>1</b>), named ADAM. ADAM shows a clear receptor preference and significant dose-dependent activation of PPARα (EC<sub>50</sub> = 47 µM) through its ligand-binding domain (LBD). Moreover, ADAM induces expression of important PPARα target genes, such as <i>CPT1A</i>, 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.en_US
dc.description.sponsorshipFRIPRO-FRINATEK 230,470en_US
dc.descriptionSource at <a href=https://doi.org/10.1016/j.bmc.2019.07.032>https://doi.org/10.1016/j.bmc.2019.07.032. </a>en_US
dc.identifier.citationArnesen, 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. <i>Bioorganic & Medicinal Chemistry, 27</i>(18), 4059-4068. https://doi.org/10.1016/j.bmc.2019.07.032en_US
dc.identifier.cristinIDFRIDAID 1718462
dc.identifier.doi10.1016/j.bmc.2019.07.032
dc.identifier.issn0968-0896
dc.identifier.issn1464-3391
dc.identifier.urihttps://hdl.handle.net/10037/16078
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalBioorganic & Medicinal Chemistry
dc.relation.projectIDinfo: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//en_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.subjectPeroxisome proliferator activated receptoren_US
dc.subjectAgonisten_US
dc.subjectOxohexadecenoic aciden_US
dc.subjectIsoxazoleen_US
dc.subjectLipid-loweringen_US
dc.subjectMicroalgaeen_US
dc.subjectChaetoceros karianusen_US
dc.titleMolecular modelling, synthesis, and biological evaluations of a 3,5-disubstituted isoxazole fatty acid analogue as a PPARα-selective agonisten_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


File(s) in this item

Thumbnail
Thumbnail

This item appears in the following collection(s)

Show simple item record