Structurally diverse indole alkaloids from an endolichenic fungus Aspergillus sp. with antiproliferative activity against non-small cell lung cancer cells.

Abstract

Chemical investigation of the endolichenic fungus Aspergillus sp. TJ403-YJ22 led to the isolation and characterization of twelve new indole alkaloids, asperkaloids A-L (1-12). Compounds 1-10 represent non-paspaline-type indole-diterpenoids, whereas 11 and 12 are polyketide-indole hybrids. Notably, compounds 1 and 2 possess a rare 2-seco-3-ketone motif. Their structures, including the constitutional frameworks and absolute configurations, were elucidated through an integrated analysis of NMR and HRESIMS data, metal-complexation ECD experiments, ECD calculations, and single-crystal X-ray diffraction analysis. In addition, re-examination of the previously reported asperdole D led to the revision of its tetrahydropyran ring to an oxepane moiety. In cell-based assays, asperkaloid F (6, AKF) exhibited growth-inhibitory activity against A549 and H1299 cells and markedly suppressed clonogenic growth, migration, and invasion, while inducing G2/M cell-cycle arrest and mitochondria-mediated apoptosis. Mechanistic investigations further revealed that AKF treatment reduced EGFR expression and attenuated the phosphorylation of key components of the EGFR/PI3K/AKT signaling pathway. Collectively, these findings expand the structural diversity of fungal indole alkaloids and identify AKF as a promising bioactive lead for further target validation and in vivo evaluation.