Magnolol dimer-derived fragments as PPARγ-selective probes

Dominik Dreier; Mirta Resetar; Veronika Temml; Lukas Rycek; Nicolas Kratena; Michael Schnürch; Daniela Schuster; Verena M. Dirsch; Marko D. Mihovilovic

doi:10.1039/C8OB01745J

Magnolol dimer-derived fragments as PPARγ-selective probes†

Dominik Dreier,

^a Mirta Resetar,

^b Veronika Temml,

^c Lukas Rycek,

^a Nicolas Kratena,

^a Michael Schnürch,

^a Daniela Schuster,

^de Verena M. Dirsch

^b and Marko D. Mihovilovic

*^a

Author affiliations

* Corresponding authors

^a Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, A-1060 Vienna, Austria
E-mail: marko.mihovilovic@tuwien.ac.at

^b Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria

^c Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria

^d Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria

^e Paracelsus Medical University Salzburg, Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Strubergasse 21, 5020 Salzburg, Austria

Abstract

Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand–target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ's heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist.

This article is part of the themed collection: Chemical Biology in OBC

Organic & Biomolecular Chemistry

Magnolol dimer-derived fragments as PPARγ-selective probes†

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