Aculeapyridones A‑Q, Pyranopyridone Alkaloids with Protective Effects against Acetaminophen-Induced Acute Liver Injury Discovered from a Coculture of Aspergillus aculeatinus WHUF0198 and a Penicillium sp.

In the search for novel natural products with hepatoprotective effects against acetaminophen-induced acute liver injury, the marine-derived fungus Aspergillus aculeatinus WHUF0198 was investigated. Seventeen undescribed pyranopyridone alkaloids, aculeapyridones A–Q (1–17), were isolated by bioactivity-guided fractionation of an extract obtained by coculture of the A. aculeatinus WHUF0198 with the mangrove-associated fungus Penicillium sp. DM27. Notably, compounds 12–15, which possessed a unique N-methoxy group, were identified as activation products of fungal coculture in liquid media. The structures and absolute configurations of these compounds were elucidated using a combination of universal spectroscopic techniques (NMR and HR-ESI-MS), ECD calculations, and single crystal X-ray diffraction analysis. All the isolated compounds, except 8 and 17, were evaluated for their hepatoprotective activity against acetaminophen-induced acute liver injury in vitro. Compounds 1–7, 9, 10 and 12–15 increased cell viability and reduced alanine aminotransferase (ALT) levels of acetaminophen-induced murine hepatocytes at either 5 or 10 μM.