Polyketide Derivatives from the Macroalga-Associated Fungus <i>Penicillium sclerotiorum</i> Exhibiting Anti-Lymphangiogenic Effect

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