Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Macakurzin C Derivatives as a Novel Pharmacophore for Pan-Peroxisome Proliferator-Activated Receptor Modulator

  • Hyejin Ko (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Seungchan An (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Hongjun Jang (Research Institute of Pharmaceutical Science and Technology, College of Pharmacy, Ajou University) ;
  • Sungjin Ahn (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • In Guk Park (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Seok Young Hwang (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Junpyo Gong (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Soyeon Oh (College of Pharmacy, Natural Products Research Institute, Seoul National University) ;
  • Soo Yeon Kwak (Research Institute of Pharmaceutical Science and Technology, College of Pharmacy, Ajou University) ;
  • Won Jun Choi (College of Pharmacy, Dongguk University-Seoul) ;
  • Hyoungsu Kim (Research Institute of Pharmaceutical Science and Technology, College of Pharmacy, Ajou University) ;
  • Minsoo Noh (College of Pharmacy, Natural Products Research Institute, Seoul National University)
  • Received : 2022.07.19
  • Accepted : 2022.09.05
  • Published : 2023.05.01
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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 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.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT) [NRF-2019R1A2C2085749, NRF-2022M3A9B6017654, and NRF-2020R1A2C2010329].

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