Format

Send to

Choose Destination
Bioorg Med Chem. 2016 Mar 15;24(6):1191-203. doi: 10.1016/j.bmc.2016.01.045. Epub 2016 Jan 23.

The molecular structure of thio-ether fatty acids influences PPAR-dependent regulation of lipid metabolism.

Author information

1
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
2
Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Imperial College London, UK; Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India.
3
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway.
4
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Norway.
5
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Norway.
6
Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Imperial College London, UK; Institute of Pharmaceutical Science, Franklin-Wilkins Building, King's College London, UK.
7
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India.
8
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India; Institute of Pharmaceutical Science, Franklin-Wilkins Building, King's College London, UK; GlobalAcorn Ltd, London, UK.
9
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway. Electronic address: jon.skorve@k2.uib.no.

Abstract

Thio-ether fatty acids (THEFAs), including the parent 2-(tetradecylthio)acetic acid (TTA), are modified fatty acids (FAs) that have profound effects on lipid metabolism given that they are blocked for β-oxidation, and able to act as peroxisome proliferator-activated receptor (PPAR) agonists. Therefore, TTA in particular has been tested clinically for its therapeutic potential against metabolic syndrome related disorders. Here, we describe the preparation of THEFAs based on the TTA scaffold with either a double or a triple bond. These are tested in cultured human skeletal muscle cells (myotubes), either as free acid or following esterification as phospholipids, lysophospholipids or monoacylglycerols. Metabolic effects are assessed in terms of cellular bioavailabilities in myotubes, by FA substrate uptake and oxidation studies, and gene regulation studies with selected PPAR-regulated genes. We note that the inclusion of a triple bond promotes THEFA-mediated FA oxidation. Furthermore, esterification of THEFAs as lysophospholipids also promotes FA oxidation effects. Given that the apparent clinical benefits of TTA administration were offset by dose limitation and poor bioavailability, we discuss the possibility that a selection of our latest THEFAs and THEFA-containing lipids might be able to fulfill the therapeutic potential of the parent TTA while minimizing required doses for efficacy, side-effects and adverse reactions.

KEYWORDS:

Diabetes type 2; Glycerolipids; Metabolic syndrome; PPAR receptors; THEFAs; TTA; Thio-ether fatty acids; β-Oxidation

PMID:
26874397
DOI:
10.1016/j.bmc.2016.01.045
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center