Toluquinol-Derived Meroterpenoids from an Engineered Aspergillus oryzae Harboring Key Biosynthetic Genes from Carnivorous Fungus Arthrobotrys oligospora.

Engineered Aspergillus oryzae strains possessing four biosynthetic genes (AOL_s00215g276-279) from carnivorous fungus Arthrobotrys oligospora enabled the isolation of 17 toluquinol-derived meroterpenoids. Thirteen were previously undescribed, including (±)-spinulinoid G (1a/1b), (±)-kuhistanol H (2a/2b), (±)-anthoponoid J (3a/3b), (±)-anthoponoid K (4a/4b), (+)-nitrosporeunol E (5a), (E)-2-methyl-3'-methoxyfarnesyl toluquinol (6), methylfarnesylquinone B (7), methylfarnesylquinone C (8), and didehydroconicol B (9), along with four known analogues (5b, 10-12). Their structures were elucidated by extensive spectroscopic analyses, and the absolute configurations were assigned by TDDFT-ECD calculations and/or comparison of optical rotation data with those of structurally related compounds. Several compounds (2a, 2b, 4a, 10, and 12) exhibited cytotoxic activity against human cancer cell lines BGC803, HCT116, MIA PaCa-2, and HeLa. Compound 2b showed prominent cytotoxicity against HCT116 and HeLa cells, with IC50 values of 7.69 μM and 5.60 μM, respectively. Furthermore, network pharmacology highlighted compounds 2b and 4a and suggested HIF1A and PIK3CA as candidate targets, for which molecular docking predicted plausible binding modes. These findings expand meroterpenoid structural diversity and provide promising small-molecule scaffolds for anticancer lead development.