Anti-Inflammatory Furylidene Tetronic Acid Derivatives from an Endophytic Fungus <i>Hypoxylon monticulosum</i> ZZ14

Naturally occurring furylidene tetronic acids were rare and structurally unique, typically with a furylidene connected to a furan-2,4-(3<i>H</i>, 5<i>H</i>)dione (tetronic acid moiety). In the current study, seven furylidene tetronic acid derivatives (<b>1</b>-<b>7</b>) were isolated and identified from the endophytic fungus <i>Hypoxylon monticulosum</i> ZZ14, including three new ones, hypoxytetronic acids A and B (<b>1</b> and <b>2</b>) and 2',3'-dihydronodulisporacid A methyl ester (<b>3</b>). Compounds <b>1</b> and <b>2</b> 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 (<b>7</b>) 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.