1. Academic Validation
  2. Discovery of Pan-peroxisome Proliferator-Activated Receptor Modulators from an Endolichenic Fungus, Daldinia childiae

Discovery of Pan-peroxisome Proliferator-Activated Receptor Modulators from an Endolichenic Fungus, Daldinia childiae

  • J Nat Prod. 2022 Dec 23;85(12):2804-2816. doi: 10.1021/acs.jnatprod.2c00791.
Jaekyeong Kim 1 Hyejin Ko 1 Jae-Seoun Hur 2 Seungchan An 1 Jin Woo Lee 3 Stephen T Deyrup 4 Minsoo Noh 1 Sang Hee Shim 1
Affiliations

Affiliations

  • 1 Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Korean Lichen Research Institute, Sunchon National University, Suncheon 57922, Republic of Korea.
  • 3 College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea.
  • 4 Department of Chemistry and Biochemistry, Siena College, Londonville, New York 12211, United States.
Abstract

Adiponectin-synthesis-promoting compounds possess therapeutic potential to treat diverse metabolic diseases, including obesity and diabetes. Phenotypic screening to find adiponectin-synthesis-promoting compounds was performed using the adipogenesis model of human bone marrow mesenchymal stem cells. The extract of the endolichenic fungus Daldinia childiae 047215 significantly promoted Adiponectin production. Bioactivity-guided isolation led to 13 active polyketides (1-13), which include naphthol monomers, dimers, and trimers. To the best of our knowledge, trimers of naphthol (1-4) have not been previously isolated as either natural or synthetic products. The novel naphthol trimer 3,1',3',3″-ternaphthalene-5,5',5″-trimethoxy-4,4',4″-triol (2) and a dimer, nodulisporin A (12), exhibited concentration-dependent adiponectin-synthesis-promoting activity (EC50 30.8 and 15.2 μM, respectively). Compounds 2 and 12 bound to all three Peroxisome Proliferator-activated Receptor (PPAR) subtypes, PPARα, PPARγ, and PPARδ. In addition, compound 2 transactivated retinoid X receptor α, whereas 12 did not. Naphthol oligomers 2 and 12 represent novel pan-PPAR modulators and are potential pharmacophores for designing new therapeutic agents against hypoadiponectinemia-associated metabolic diseases.

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