Azaphilone derivatives with RANKL-induced osteoclastogenesis inhibition from the mangrove endophytic fungus Diaporthe sp.

Six structurally diverse new azaphilones, isochromophilones G−L (1−6), and three new biosynthetically related congeners (7−9) were obtained from Diaporthe sp. SCSIO 41011. Their structures including absolute configurations were determined by comprehensive spectroscopic analyses along with experimental and calculated ECD spectra. Notably, three highly oxygenated azaphilones harbor an acetyl group attached at the terminal chain (4) or linear conjugated polyenoid moieties (5 and 6), which are relatively rare in the azaphilone family. Moreover, several of them exhibited inhibition of lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-κB) activation in RAW 264.7 macrophages at 20 μM. The new potent compound (1) further suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation without observed cytotoxicity in bone marrow and RAW 264.7 macrophages, suggesting a promising lead compound for the treatment of osteolytic diseases. To our knowledge, this is the first report of azaphilone derivatives as inhibitors of RANKL-induced osteoclastogenesis.