Polyketide Derivatives from the Macroalga-Associated Fungus Penicillium sclerotiorum Exhibiting Anti-Lymphangiogenic Effect

Integrating genome mining with LC-MS/MS-based molecular networking analysis has revealed that the extract of the endophytic fungus Penicillium sclerotiorum represents a promising source for the discovery of new azaphilone analogues. Two rare polyketide derivatives (1 and 2), along with 11 new sclerotiorin-type azaphilones (3-13) and eight known compounds (14-21), were isolated from the macroalga-associated fungus P. sclerotiorum. The structural elucidation of these compounds was achieved using ECD, HR-ESI-MS, and NMR spectroscopic analyses. The absolute configurations of compounds 1 and 2 were determined through X-ray single-crystal diffraction. The antilymphangiogenic potential of these isolates was assessed in vitro using human lymphatic endothelial cells (LECs). Compounds 4 and 14, both nitrogenated azaphilones, exhibited significant inhibitory activity, displaying IC₅₀ values of 5.7 ± 0.2 and 5.8 ± 0.2 μg/mL, respectively.