Identifying Marine-Derived Tanzawaic Acid Derivatives as Novel Inhibitors against Osteoclastogenesis and Osteoporosis via Downregulation of NF-κB and NFATc1 Activation.

To discover novel osteoclast-targeting antiosteoporosis leads from natural products, we identified 40 tanzawaic acid derivatives, including 22 new ones ( 1 - 8 , 14 - 19 , 27 - 32 , 37 , and 38 ), from the South China Sea mangrove-derived fungus Penicillium steckii SCSIO 41025. Penicisteck acid F ( 2 ), one of the new derivatives showing the most potent NF-κB inhibitory activity, remarkably inhibited osteoclast generation in vitro . Mechanistically, 2 reduced RANKL-induced IκBα degradation, NF-κB p65 nuclear translocation, the activation and nuclear translocation of NFATc1, and the relevant mRNA expression. NF-κB p65 could be a potential molecular target for 2 , which has been further determined by the cellular thermal shift assay, surface plasmon resonance, and the gene knock-down assay. Moreover, 2 could also alleviate osteoporosis in ovariectomized mice by reducing the quantities of osteoclasts. Our finding offered a novel potential inhibitor of osteoclastogenesis and osteoporosis for further development of potent antiosteoporosis agents.