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.
Highlights
PPARs (Peroxisome Proliferator-Activated Receptors) are members of the nuclear receptor family of transcription factors
The rationale for the synthesis of the sesqui target compounds III and IV is in line with the reported synthetic route towards magnolol dimer (II) and is depicted in Scheme 1
The new ligands have been successfully synthesized in a straight-forward fashion
Summary
PPARs (Peroxisome Proliferator-Activated Receptors) are members of the nuclear receptor family of transcription factors. They require ligand-binding and heterodimerization with the nuclear receptor RXR (Retinoid X Receptor) to activate gene transcription. Current efforts are directed towards developing selective PPAR agonists, which would activate desired physiological responses in tissues of interest, exclusively. It has been shown that different partial agonists cause distinct conformational changes that lead to different coactivator recruitment and activation of discrete sets of genes.[3] In this work, we report a rational design approach and synthesis towards new synthetic ligands, derived from the structure of the known PPARγ agonist magnolol (I) and magnolol dimer (II), developed previously in our laboratory, employing a modified fragment approach (Fig. 1).[6]
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