Isolation and total synthesis of a cytotoxic polyketide lead from Aspergillus sp. YUD22001 associated with Panax notoginseng rhizosphere.

A chemical investigation of Aspergillus sp. YUD22001, a rhizosphere-derived fungus isolated from diseased Panax notoginseng roots, resulted in the discovery of two new polyketides, asperketones A (1) and B (2), alongside seven known secondary metabolites (3-9). The structures of these compounds were unambiguously determined through comprehensive spectroscopic analyses. Asperketone A (1) demonstrated broad-spectrum cytotoxicity against four human cancer cell lines with IC50 values ranging from 6.1 to 29.4 μM. Notably, it exhibited significantly greater potency than cisplatin against A549, SMMC-7721 and MDA-MB-231 cells, while displaying reduced cytotoxicity toward normal bronchial epithelial cells (BEAS-2B). In contrast, asperketone B, which bears a methyl acetate substituent instead of the butan-2-one chain, showed negligible activity (IC50 > 50 μM), underscoring the structural importance of the butan-2-one pharmacophore. Molecular docking implicated lactate dehydrogenase A (LDHA) as a potential target, with 1 forming key hydrogen bonds via its ketone carbonyl. A scalable total synthesis of 1 was achieved via a boronate-mediated coupling strategy, enabling gram-scale production. This study highlights the underexplored potential of rhizospheric fungi as sources of bioactive natural products and demonstrates the synergistic integration of natural product discovery, synthetic methodology, and computational biology for anticancer drug development.