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.