Antiosteoclastogenic Indole Alkaloids from the Mangrove Endophytic Fungus Penicillium brefeldianum GXIMD 02511

Eight new prenylated indole alkaloids, brefeldindoles A–F (1–6), G (8), and H (11), together with 17 known analogues, were obtained from the Beibu Gulf mangrove-derived fungal strain Penicillium brefeldianum GXIMD 02511. Their structures, including absolute configurations, were determined by analysis of spectroscopic data and electronic circular dichroism (ECD) calculations. Brefeldindoles A–F (1–6) are characterized as a rare class of indole-diterpenoid derivatives with uncommon 3-methyl-3-hydroxybutyl substituents in the benzene ring. Brefeldindole H (11) is the first example of an unprecedented 6/5/6/6/6/5-fused indole-diketopiperazine. Most alkaloids inhibited lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-κB) activation in RAW264.7 macrophages at 20 μM. Preliminary structure–activity relationships are discussed. Compounds 5, 6, and 16 suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation without observed cytotoxicity in bone marrow macrophages (BMMs). Compound 5 significantly inhibited NF-κB activation, leading to the suppression of nuclear translocation of NFATc1 and downregulation of the expression of osteoclast-related fusion protein DC-STAMP. Our findings indicated compound 5 as a potential inhibitor of osteoclast differentiation for the treatment of bone destruction-related diseases.