Peniditerpenoids A and B: Oxidized Indole Diterpenoids with Osteoclast Differentiation Inhibitory Activity from a Mangrove-Sediment-Derived Penicillium sp

An unprecedented di-seco-indole diterpenoid, peniditerpenoid A (1), and a rare N-oxide-containing indole diterpenoid derivative, peniditerpenoid B (2), together with three known ones (3-5), were obtained from the mangrove-sediment-derived fungus Penicillium sp. SCSIO 41411. Their structures were determined by the analysis of spectroscopic data, quantum chemical calculations, and X-ray diffraction analyses. Peniditerpenoid A (1) inhibited lipopolysaccharide-induced NF-κB with an IC₅₀ value of 11 μM and further effectively prevented RANKL-induced osteoclast differentiation in bone marrow macrophages. In vitro studies demonstrated that 1 exerted significant inhibition of NF-κB activation in the classical pathway by preventing TAK1 activation, IκBα phosphorylation, and p65 translocation. Furthermore, 1 effectively reduced the level of NFATc1 activation, resulting in the attenuation of osteoclast differentiation. Our findings suggest that 1 holds promise as an inhibitor with significant potential for the treatment of diseases related to osteoporosis.