PI3K-inhibitory new anthraquinone-xanthone heterodimers from a deep-sea Epichloe sp. SCSIO 41042

Two new xanthone-anthraquinone heterodimers (1 and 2), and eleven known anthraquinones (3-13) were isolated from the deep-sea derived Epichloe sp. SCSIO 41042 fermented on rice medium. Structurally, compounds 1-5 feature a unique bicyclo[3.2.2]nonane core formed through dual CC linkages. Their structures and absolute configurations were determined by spectroscopic analyses and calculated electronic circular dichroism (ECD). Molecular docking was performed to characterize the affinity of anthraquinones for phosphatidylinositol 3-kinase (PI3K), identifying those with significant anti-PI3K activity. Active compounds were subsequently profiled via homogeneous time-resolved fluorescence (HTRF) assay for PI3K inhibition, followed by binding affinity validation using surface plasmon resonance (SPR). Activity assay revealed that 2 significantly inhibited both PI3Kα^WT and PI3Kα^H1047R enzymes, with IC₅₀ values of 2.00 and 3.42 μM, respectively. Further SPR analysis demonstrated a moderate binding affinity between 2 and PI3K, with a K_D of 12.7 μM.