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

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.

Discovery of Naphthol Tetramers from Endolichenic Fungus Daldinia childiae 047219 Based on MS/MS Molecular Networking

“…Compounds 2 , 4 , and 5 showed exactly two sets of NMR resonances, although they were isolated as a single peak using preparative HPLC, while compounds 1 , 3 , and 6 exhibited just one set of signals in the NMR (Tables and ). As reported in our previous publications, biaryl compounds with ortho substituents (only the two OH groups) next to the biaryl linkage have a very low rotational barrier at the axis and they cannot exist as two stable atropisomeric forms at room temperature as shown in 1 , 3 , and 6 . However, biaryl compounds with ortho – para and para – para substituents occur as a pair of configurationally semistable and slowly interconverting atropisomers, as shown in 2 , 4 , and 5 .…”

“…Nodes with an identical m/z value of 519.3 in subcluster MN2 (Figure 1) were also observed. Those were assumed to be trimers of naphthol, and it was confirmed using the compounds previously isolated; 5 four spectral nodes were identified as 1,1′,3′,3″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (16), 3,1′,3′,3″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (17), 1,1′,3′,1″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (18), and 3,1′,3′,1″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (19). Multiple spectral nodes in the subcluster MN3 exhibited the m/z value of 691.4, which were suggested to be naphthol tetramers (Figure 1); interpretation of the MS/MS spectra represented by these spectral nodes supported this hypothesis.…”

“…Endolichenic fungi have been reported to produce substances exhibiting various bioactivities including cytotoxic, antiviral, and antibacterial activity. − We previously reported monomers, dimers, and new trimers of 8-methoxy-1-naphthol with adiponectin-synthesis-promoting action from the endolichenic fungus Daldinia childiae 047215 . We looked for additional patterns of oligomerization in products from our in-house endolichenic fungal library since the biological activity depending on the oligomerization pattern was intriguing, and additional new analogues may be present.…”

“…1−4 We previously reported monomers, dimers, and new trimers of 8-methoxy-1naphthol with adiponectin-synthesis-promoting action from the endolichenic fungus Daldinia childiae 047215. 5 We looked for additional patterns of oligomerization in products from our in-house endolichenic fungal library since the biological activity depending on the oligomerization pattern was intriguing, and additional new analogues may be present. To accomplish this, we employed a molecular networking system 6,7 based on the MS−MS fragmentation pattern of the molecules, which suggested one strain may produce naphthol tetramers which have not been previously reported from nature.…”

“…By interpretation of NMR and MS spectroscopic data, compounds 1−6, tetramers of naphthol, were characterized. By comparing our NMR spectroscopic data with those in the literature, other compounds that were identified are 1,8-dimethoxy naphthalene (7), 9 8-methoxy 1naphthol (8), 10 5-hydroxy-2-methyl-4H-chromen-4-one (9), 11 1-(2,6-dihydroxyphenyl) butan-1-one (10), 12 2,6-dihydroxyacetophenone (11), 13 nodulisporin E (15), 14 daldinol (12), 15 nodulisporin A (13), 16 nodulisporin B (14), 16 1,1′,3′,3″-87 ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (16), 5 3,1′,3′,3″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (17), 5 1,1′,3′,1″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″triol (18), 5 and 3,1′,3′,1″-ternaphthalene-5,5′,5″-trimethoxy-4,4′,4″-triol (19), 5 respectively. The isolated compounds were naphthol derivatives.…”