Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands

Rýček, Lukáš; Puthenkalam, Roshan; Schnürch, Michael; Ernst, Margot; Mihovilovic, Marko D.

doi:10.1016/j.bmcl.2014.10.091

Cited by 11 publications

(13 citation statements)

References 21 publications

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“…For subsequent biological studies, a modular synthetic strategy was developed towards structural analogs of 3 and 6 based on cross coupling chemistry [ 28 ] (Fig. 4 ).…”

Section: Selected Findings Of the Dnti Projectmentioning

confidence: 99%

Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project

et al. 2016

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Inflammation is part of numerous pathological conditions, which are lacking satisfying treatment and effective concepts of prevention. A national research network project, DNTI, involving scientists from six Austrian universities as well as several external partners aimed to identify and characterize natural products capable of combating inflammatory processes specifically in the cardiovascular system. The combined use of computational techniques with traditional knowledge, high-tech chemical analysis and synthesis, and a broad range of in vitro, cell-based, and in vivo pharmacological models led to the identification of a series of promising anti-inflammatory drug lead candidates. Mechanistic studies contributed to a better understanding of their mechanism of action and delivered new knowledge on the molecular level of inflammatory processes. Herein, the used approaches and selected highlights of the results of this interdisciplinary project are presented.Graphical abstract

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“…For subsequent biological studies, a modular synthetic strategy was developed towards structural analogs of 3 and 6 based on cross coupling chemistry [ 28 ] (Fig. 4 ).…”

Section: Selected Findings Of the Dnti Projectmentioning

confidence: 99%

Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project

et al. 2016

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“…Magnolol ( I ) is a lignan found in the bark of the plant Magnolia officinalis which has been used in traditional Chinese medicine as potential anti-inflammatory, anti-cancer, and neuromodulatory agent as well as a lead structure for synthetic derivatives. 7 , 8 We previously demonstrated that magnonol ( I ) is a partial PPARγ agonist. 9 However, magnolol ( I ) was found to activate RXRα as well.…”

Section: Introductionmentioning

confidence: 99%

Magnolol dimer-derived fragments as PPARγ-selective probes

et al. 2018

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“…This work focused on the ambition to further exploit the biaryl-system of magnolol and honokiol in order to create selective PPARγ ligands 12 with no concomitant effect on RXRα. We made use of the recent report on the co-crystallization of magnolol with the ligand binding domains of RXRα and PPARγ 10 .…”

Section: Introductionmentioning

confidence: 99%

Linked magnolol dimer as a selective PPARγ agonist – Structure-based rational design, synthesis, and bioactivity evaluation

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et al. 2017

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The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (K i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.

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Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands

Abstract: Graphical abstract

Cited by 11 publications

References 21 publications

Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project

Drugs from nature targeting inflammation (DNTI): a successful Austrian interdisciplinary network project

Magnolol dimer-derived fragments as PPARγ-selective probes

Linked magnolol dimer as a selective PPARγ agonist – Structure-based rational design, synthesis, and bioactivity evaluation

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