Phaeosphaones: Tyrosinase Inhibitory Thiodiketopiperazines From An Endophytic Phaeosphaeria Fuckelii

Phaeosphaeria fuckelii, an endophytic fungus associated with the herbal medicine Phlomis umbrosa, produced four new thiodiketopiperazine alkaloids, phaeosphaones A-D (1-4), featuring an unusual beta-(oxy)thiotryptophan motif, along with four known analogues, phaeosphaone E (5), chetoseminudin B (6), polanrazine B (7), and leptosin D (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. Compounds 4, 6, and 8 were found to display mushroom tyrosinase inhibitory activity with IC50 values of 33.2 +/- 0.2, 31.7 +/- 0.2, and 28.4 +/- 0.2 mu M, respectively, more potent than that of the positive control, kojic acid (IC50 = 40.4 +/- 0.1 mu M). A molecular-docking study disclosed the pi-pi stacking interaction between the indole moiety of 8 and the His243 residue of tyrosinase.