Spiroeutypetides A and B, Polyketides with 5/6/5 and 6/6/5 Tricyclic Ring Systems Produced by the Marine-Derived Fungus <i>Eutypella</i> sp. F0219

Four previously undescribed polyketides, spiroeutypetides A-B (<b>1</b>-<b>2</b>), eutypetide I (<b>3</b>), and eutypetide J (<b>4</b>), were isolated from the rice culture of the marine-derived fungus <i>Eutypella</i> sp. F0219. Of these, compounds <b>1</b>-<b>3</b> possess unprecedented carbon skeletons, whereas <b>4</b> is a new polycyclic 10-membered lactone. The structures, including absolute configurations, were elucidated via spectroscopic data analysis, modified Mosher's method, X-ray crystallography, GIAO ¹³C NMR (DP4+) calculations, and ECD calculations. Spiroeutypetides A (<b>1</b>) and B (<b>2</b>) are two novel C₁₆ polyketides featuring distinct spirocyclization patterns, forming 5/6/5 and 6/6/5 tricyclic systems, respectively, whereas eutypetide I (<b>3</b>) is the first C₁₆ polyketide characterized by cleavage of the C4-C5 bond. All compounds were evaluated for their inhibitory effects on NO production in lipopolysaccharide-activated BV2 microglial cells. Eutypetide J (<b>4</b>) exhibited significant antineuroinflammatory activity by inhibiting microglial polarization and suppressing inflammasome-related proteins, including NLRP3 and caspase 1.