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.