Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects

• Published in: European Journal of Medicinal Chemistry
• Main Authors: Sæther, Thomas, Paulsen, Steinar M, Tungen, Jørn Eivind, Vik, Anders, Aursnes, Marius, Holen, Torgeir, Hansen, Trond Vidar, Nebb, Hilde Irene
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier 2018
• Subjects: VDP::Medical disciplines: 700::Basic medical; dental and veterinary science disciplines: 710; VDP::Medisinske Fag: 700::Basale medisinske; odontologiske og veterinærmedisinske fag: 710; Arctic
• Online Access: https://hdl.handle.net/10037/15305; https://doi.org/10.1016/j.ejmech.2018.06.034

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.