Penimeroandranoid E, an Uncommon 6/6/6/5 Spirocyclic Meroterpenoid from the Deep-Sea-Derived Fungus Penicillium mali, Inhibits Osteoclastogenesis

Chemical investigation of the deep-sea-derived fungusPenicillium maliMCCC 3A00140 afforded two new compounds, penimeroandranoid E (1) and malistatin (2), together with 16 known ones (3–18). Their structures were established by extensive spectroscopic analyses, including 1D and 2D NMR and HRESIMS. The relative configuration of1was supported by single-crystal X-ray diffraction, and its absolute configuration was assigned by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Compound1was the meroterpenoid reported to possess a 6/6/6/5 spirocyclic framework—a spiro-fused variant of the 6/6/6/5 carbocyclic system that was characteristic of andrastin-type DMOA-derived meroterpenoids—and its structure and relative configuration were established by single-crystal X-ray diffraction. The stereochemical assignment of2was based on NOESY correlations and biosynthetic analogy with related statins. Screening of all isolates at 20 μM in a receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis model using primary murine bone marrow-derived macrophages identified1as the bioactive secondary metabolite. Compound1reduced the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts at 12.5–50 μM without decreasing cell viability after 48 h at concentrations up to 50 μM. These findings expand the chemical diversity of fungal meroterpenoids and identify1as a structurally distinctive anti-osteoclastogenic metabolite warranting further mechanistic investigation.