Hyperwilsol A, a highly modified 2-nor-polycyclic polyprenylated acylphloroglucinol possessing an unusual 6/6/5/5 spirotetracyclic skeleton from Hypericum wilsonii.

Hypericum species are rich in polycyclic polyprenylated acylphloroglucinols (PPAPs), a class of structurally complex metabolites with diverse biological activities. A phytochemical investigation of the aerial parts of Hypericum wilsonii led to the discovery of four previously undescribed PPAPs, hyperwilsols A-D (1-4), along with 16 known related compounds (5-20). Notably, hyperwilsol A (1) featured a highly modified 6/6/5/5 tetracyclic system based on a rare spiro[1,2-dioxane-3,11'-[3,12]dioxatricyclo[6.4.0.01,5]dodecane] scaffold. The structures with absolute configurations were established by spectroscopic analysis, computer-assisted structure elucidation method, single-crystal X-ray diffraction, and NMR and ECD calculations. Additionally, all isolates were evaluated for their anti-neuroinflammatory and neuroprotective effects. Hyperuralone A (16) and yezo'otogirin A (17) exhibited inhibition of lipopolysaccharide-induced nitric oxide production in BV-2 cells, with their IC50 values of 7.11 ± 0.50 and 10.18 ± 1.75 μM, respectively. Hyperwilsols A-C (1-3), hyperscabin K (9), and hypelodin B (10) showed noticeable neuroprotective activity against H2O2-induced PC-12 cell injury. These findings not only enriched the structural diversity of natural PPAPs but also highlighted their potential in the prevention and treatment of neurodegenerative diseases.