Isolation of lingzhifuran A and lingzhilactones D–F from Ganoderma lucidum as specific Smad3 phosphorylation inhibitors and total synthesis of lingzhifuran A

Lingzhifuran A (1) and lingzhilactones D–F (2–4), four new phenolic meroterpenoids were isolated from the fruiting bodies of Ganoderma lucidum. Their structures were identified by spectroscopic data. Chiral HPLC analysis indicates the racemic nature of 2–4. Chiral separation followed by X-ray diffraction analysis discloses the absolute configuration of (−)-2. Compounds 1 and 2 could selectively inhibit TGF-β1-induced Smad3 phosphorylation in rat renal tubular epithelial cells, representing novel scaffolds of selective Smad3 activation inhibitors. Total synthesis accompanied by in vivo rodent experiments reveals antifibrotic activities of 1 against kidney fibrosis. Finally, a plausible biosynthetic pathway for 1 was proposed.