Spiro-Linked Polyketides from Cultures of Westerdykella dispersa Ca4-13 as Inhibitors of iNOS-Associated Neuroinflammation.

Chemical investigation on fermented products by the fungal strain Westerdykella dispersa Ca4-13 isolated from edible oysters Crassostrea angulata collected from Taiwan resulted in the isolation of seven chemical entities. Their structures were elucidated by spectroscopic analysis to be westeroic acid A (1), westeroic acid B (2), westeroic acid C (3), auranticin A (4), auranticin B (5), pilobolusone C (6), and epi-radicinol (7). Among these, westeroic acid A (1) is a novel C14 polyketide with a γ-lactone functionality, while westeroic acids B (2) and C (3) are two rare C28 polyketides with a unique 6/6-spiro-linked δ-lactone moiety. Compounds 1, 2, 3, and 7 exhibited anti-inflammatory activities on nitric oxide production in lipopolysaccharide (LPS)-induced BV-2 microglial cells with IC50 values ranging from 9.9 to 11.3 μM. Compounds 2 and 3 significantly suppressed LPS-induced inducible nitric oxide synthase (iNOS) protein expression. Molecular docking analysis using murine iNOS (PDB ID: 1QW4) provided structural insight into these observations, suggesting that effective inhibition was associated with cooperative interaction networks within the l-arginine binding pocket rather than a single dominant interaction. Overall, these findings highlight their promise as potential lead compounds for further neuroinflammation-related drug development.