Biomol Ther.  2023 May;31(3):312-318. 10.4062/biomolther.2022.097.

Macakurzin C Derivatives as a Novel Pharmacophore for Pan-Peroxisome Proliferator-Activated Receptor Modulator

• Ko H
• An S
• Jang H
• Ahn S
• Park IG
• Hwang SY
• Gong J
• Oh S
• Kwak SY
• Choi WJ
• Kim H
• Noh M

• KMID: 2541790
• DOI: http://doi.org/10.4062/biomolther.2022.097

Abstract

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 biosynthesisinducing 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.

Keyword

Macakurzin C derivative; Peroxisome proliferator-activated receptor; Adiponectin; Human bone marrow mesenchymal stem cells; PPARα/γ dual modulator