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Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ-RXR
https://gifu-pu.repo.nii.ac.jp/records/14009
https://gifu-pu.repo.nii.ac.jp/records/14009f39b2dde-0110-4269-944c-2cc52e0efb7b
| Item type | 研究室原著論文(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2020-09-08 | |||||
| タイトル | ||||||
| タイトル | Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ-RXR | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 抄録 | ||||||
| 値 | A known natural product, magnaldehyde B, was identified as an agonist of retinoid X receptor (RXR) α. Magnaldehyde B was isolated from Magnolia obovata (Magnoliaceae) and synthesized along with more potent analogs for screening of their RXRα agonistic activities. Structural optimization of magnaldehyde B resulted in the development of a candidate mol. that displayed a 440-fold increase in potency. Receptor-ligand docking simulations indicated that this mol. has the highest affinity with the ligand binding domain of RXRα among the analogs synthesized in this study. Furthermore, the selective activation of the peroxisome proliferator-activated receptor (PPAR) δ-RXR heterodimer with a stronger efficacy compared to those of PPARα-RXR and PPARγ-RXR was achieved in luciferase reporter assays using the PPAR response element driven reporter (PPRE-Luc). The PPARδ activity of the mol. was significantly inhibited by the antagonists of both RXR and PPARδ, whereas the activity of GW501516 was not affected by the RXR antagonist. Furthermore, the mol. exhibited a particularly weak PPARδ agonistic activity in reporter gene assays using the Gal4 hybrid system. The obtained data therefore suggest that the weak PPARδ agonistic activity of the optimized mol. is synergistically enhanced by its own RXR agonistic activity, indicating the potent agonistic activity of the PPARδ-RXR heterodimer. | |||||
| 書誌情報 |
en : ACS Chemical Biology 巻 15, 号 6, p. 1526-1534, 発行日 2020 |
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