Galangin 3-benzyl-5-methylether derivatives function as an adiponectin synthesis-promoting peroxisome proliferator-activated receptor γ partial agonist. (15th January 2022)

• Record Type: Journal Article
• Authors: Ko, Hyejin; Jang, Hongjun; An, Seungchan; Park, In Guk; Ahn, Sungjin; Gong, Junpyo; Hwang, Seok Young; Oh, Soyeon; Kwak, Soo Yeon; Choi, Won Jun; Kim, Hyoungsu; Noh, Minsoo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 54(2022)
• Publication Date: 2022-01-15
• Subjects: Galangin derivatives -- Peroxisome proliferator-activated receptor gamma -- Estrogen receptor beta -- Adiponectin -- Human bone marrow mesenchymal stem cells; DMEM Dulbecco Modified Eagle's Medium -- ELISA enzyme-linked immunosorbent assay -- ER estrogen receptor -- FABP4 fatty acid-binding protein 4 -- FBS fetal bovine serum -- hBM-MSCs human bone marrow mesenchymal stem cells -- LBD ligand binding domain -- MED1 Mediator of RNA polymerase II transcription subunit 1 -- PBS phosphate-buffered saline -- PDB Protein Data Bank -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1-alpha -- PPAR peroxisome proliferator-activated receptor -- PRIP/RAP250 peroxisome proliferator-activated receptor gamma-interacting protein/nuclear receptor-activating protein 250 -- Q-RT-PCR quantitative real-time reverse transcription-polymerase chain reaction -- RIP140 receptor interacting protein 140 -- SRC-3 nuclear receptor coactivator-3 -- TRAP220/DRIP-2 thyroid hormone receptor-associated protein complex 220/vitamin D receptor-interacting protein-2 -- TR-FRET time-resolved fluorescence resonance energy transfer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116564
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The upregulation of adiponectin production has been suggested as a novel strategy for the treatment of metabolic diseases. Galangin, a natural flavonoid, exhibited adiponectin synthesis-promoting activity during adipogenesis in human bone marrow mesenchymal stem cells. In target identification, galangin bound both peroxisome proliferator-activated receptor (PPAR) γ and estrogen receptor (ER) β. Novel galangin derivatives were synthesized to improve adiponectin synthesis-promoting compounds by increasing the PPARγ activity of galangin and reducing its ERβ activity, because PPARγ functions can be inhibited by ERβ. Three galangin 3-benzyl-5-methylether derivatives significantly promoted adiponectin production by 2.88-, 4.47-, and 2.76-fold, respectively, compared to the effect of galangin. The most potent compound, galangin 3-benzyl-5, 7-dimethylether, selectively bound to PPARγ ( Ki, 1.7 μM), whereas it did not bind to ERβ. Galangin 3-benzyl-5, 7-dimethylether was identified as a PPARγ partial agonist in docking and pharmacological competition studies, suggesting that it may have diverse therapeutic potential in a variety of metabolic diseases.