Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1 and 13-epi-dinor-PGD1 are peroxisome proliferator-activated receptor α/γ dual agonists

doi:10.1016/j.bmcl.2013.03.024

Bioorganic & Medicinal Chemistry Letters

Volume 23, Issue 10, 15 May 2013, Pages 3013-3017

https://doi.org/10.1016/j.bmcl.2013.03.024 Get rights and content

Abstract

2,3-Dinorprostaglandins (dinor-PGs) have been regarded as β-oxidation products of arachidonic-acid-derived prostaglandins, but their biological activities in mammalian cells remain unclear. On the other hand, C18 polyunsaturated fatty acids (PUFAs), such as γ-linolenic acid (GLA), have various biological activities, and dinor-PGs are speculated to be biosynthesized from GLA. Here, we synthesized dinor-PGs that may possibly be derived from GLA and examined their activities towards peroxisome proliferator-activated receptors (PPARs). Dinor-PGD₁ (1) and its epimer 13-epi-dinor-PGD₁ (epi-1) were found to be dual agonists for PPARα/γ, whereas PGD₂ derived from arachidonic acid is selective for PPARγ. Thus, GLA-derived dinor-PGs may have unique biological roles.

Graphical abstract

We synthesized 2,3-dinorprostaglandins, dinor-PGD₁, 13-epi-dinor-PGD₁, and 13-deoxy-Δ^10,12-dinor-PGJ₁, and examined their effects on the activity of peroxisome proliferator-activated receptors (PPARs). Dinor-PGD₁ and 13-epi-dinor-PGD₁ were dual agonists for PPARα/γ, in contrast to the highly PPARγ-selective prostaglandins derived from arachidonic acid.

Section snippets

Acknowledgment

We thank Dr. M. Ishikawa (The University of Tokyo) for helpful discussions about the docking study.

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Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1 and 13-epi-dinor-PGD1 are peroxisome proliferator-activated receptor α/γ dual agonists

Abstract

Graphical abstract

Section snippets

Acknowledgment

Prostaglandins Leukot. Essent. Fatty Acids

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Chem. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

Cell

Cell

Prostaglandins

Bioorg. Med. Chem. Lett.

Structure

J. Mol. Biol.

J. Am. Oil Chem. Soc.

Br. Med. Bull.

Proc. Natl. Acad. Sci. U.S.A.

Nature

Eicosanoids

Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD₁ and 13-epi-dinor-PGD₁ are peroxisome proliferator-activated receptor α/γ dual agonists