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 fungus Penicillium mali MCCC 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 of 1 was 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. Compound 1 was 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 of 2 was 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 identified 1 as the bioactive secondary metabolite. Compound 1 reduced 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 identify 1 as a structurally distinctive anti-osteoclastogenic metabolite warranting further mechanistic investigation.