Diorcinol L, a natural pentenyl diphenyl ether isolated from Aspergillus sp. MA6037, exhibits cytotoxic activity by inhibiting KIF11.

Fungi are important sources for the discovery and production of bioactive metabolites, many of which exhibit promising cytotoxicity against colorectal cancer (CRC). Among these, human gut-derived fungi have emerged as a valuable reservoir of natural products with cytotoxic properties. Diphenyl ethers (DEs) constitute a structurally diverse class of fungal secondary metabolites. In this study, a series of DEs, including the rarely reported prenylated diphenyl ethers (PDEs), were isolated and identified from the human gut-derived fungus Aspergillus sp. MA 6037. Using chromatographic and spectroscopic methods, along with in vitro cytotoxicity assays, we confirmed that these compounds contribute to the cytotoxic effects of the fungal extract against human colorectal (HCT116 and RKO) cancer cells. Notably, a new PDE derivative named Diorcinol L was identified. Meanwhile, the structures of Diorcinols K and L have been revised. Further investigation revealed that the cytotoxic activity of these PDEs may be related to their direct binding to kinesin family member 11 (KIF11), which in turn promotes tumor cell apoptosis. This study highlights the significance of human gut fungi as a source of bioactive metabolites, introduces new chemical entities for anti-CRC research, and establishes a foundation for developing natural product-based antitumor drugs.