Anti-Inflammatory Furylidene Tetronic Acid Derivatives from an Endophytic Fungus Hypoxylon monticulosum ZZ14

Naturally occurring furylidene tetronic acids were rare and structurally unique, typically with a furylidene connected to a furan-2,4-(3H, 5H)dione (tetronic acid moiety). In the current study, seven furylidene tetronic acid derivatives (1–7) were isolated and identified from the endophytic fungus Hypoxylon monticulosum ZZ14, including three new ones, hypoxytetronic acids A and B (1 and 2) and 2′,3′-dihydronodulisporacid A methyl ester (3). Compounds 1 and 2 possess an unusual skeleton, with two tetrahydrofurans attached to the tetronic acid moiety. Their absolute configurations were elucidated by custom-DP4+ probability analysis of NMR chemical shifts and ECD calculations. Nodulisporacid A methyl ester (7) significantly inhibited the production of interleukin 6 (IL-6), interleukin 10 (IL-10), nitric oxide (NO), and inducible nitric oxide synthase (iNOS), comparable to the positive control dexamethasone. Several analogues of nodulisporacid A methyl ester were synthesized, and structure–activity relationship studies were performed, suggesting that the conjugated fragment of 1/2/3/1′/2′/3′ and the methyl ester group may be the pharmacophores.