New Polyketides and a Ferroptosis Inhibitor from the Marine-Derived Fungus Diaporthe searlei CS-HF-1

As a driver of neurodegenerative disorders, ischemic injuries, and acute organ dysfunction, ferroptosis represents a therapeutic target, and its inhibition may provide novel therapies. In our ongoing efforts to discover ferroptosis inhibitors from fungal strains, chemical investigation of the strain Diaporthe searlei CS-HF-1 led to the isolation of four polyketide-derived alkaloids (1-3 and 17) and fourteen polyketides (4-16 and 18), including three new isoindolone derivatives (1-3), a new phthalide (4), a new butyrolactone derivative (10), and three new nonenolides (11-13). The structures were determined by comprehensive spectroscopic analysis. The structures of 1, 2, and 10 were confirmed by comparison of experimental and calculated ¹³C NMR chemical shifts. The absolute configurations of compounds 10, 11, and 14 were assigned by ECD calculations, while those of 12 and 13 were assigned based on their biogenetic relationship with 14. Notably, compound 1 represents the first isoindolone featuring a primary amide group attached to the lactam nitrogen, while compound 2 is the first naturally occurring isoindolone dimer. These compounds were assessed for the anti-ferroptotic activity. As a result, asperlactone A (15) exhibited inhibition on RSL3-induced ferroptosis in HT22 cells with an EC₅₀ of 11.3 ± 0.4 μM. Preliminary mechanistic study revealed that 15 attenuated lipid peroxidation, as evidenced by reduced MDA levels, elevated GSH content, and suppression of lipid radical generation. This study offers a new chemotype for the development of novel ferroptosis inhibitors.