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. Epub 2022 Dec 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / metabolism
  • Ascomycota* / metabolism
  • Humans
  • Naphthols
  • PPAR alpha
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptors*

Substances

  • Peroxisome Proliferator-Activated Receptors
  • Adiponectin
  • Naphthols
  • PPAR gamma
  • PPAR alpha

Supplementary concepts

  • Daldinia childiae