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KMID : 0606920230310030312
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Biomolecules & Therapeutics
2023 Volume.31 No. 3 p.312 ~ p.318
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Macakurzin C Derivatives as a Novel Pharmacophore for Pan-Peroxisome Proliferator-Activated Receptor Modulator
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Heo Ye-Ji
Jang Min-Ju
Lee Ju-Heon
Ahn Sung-Jin
Park In-Guk
Hwang Seok-Young
Gong Jun-Pyo
Oh So-Yeon
Kwak Soo-Yeon
Son Sun-Han
Kim Hyoung-Su
Park Myung-Woo
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Abstract
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The natural flavonoid macakurzin C (1) exhibited adiponectin biosynthesis-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells and its molecular mechanism was directly associated with a pan-peroxisome proliferator-activated receptor (PPAR) modulator affecting all three PPAR subtypes α, γ, and δ. In this study, increases in adiponectin biosynthesis-inducing activity by macakurzin C derivatives (2?7) were studied. The most potent adiponectin biosynthesis-inducing compound 6, macakurzin C 3,5-dimethylether, was elucidated as a dual PPARα/γ modulator. Compound 6 may exhibit the most potent activity because of the antagonistic relationship between PPARδ and PPARγ. Docking studies revealed that the O-methylation of macakurzin C to generate compound 6 significantly disrupted PPARδ binding. Compound 6 has therapeutic potential in hypoadiponectinemia-related metabolic diseases.
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KEYWORD
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Macakurzin C derivative, Peroxisome proliferator-activated receptor, Adiponectin, Human bone marrow mesenchymal stem cells, PPARα/γ dual modulator
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