A Novel (6S)-4,6-Dimethyldodeca-2E,4E-dienoyl Ester of Phomalactone and Related α-Pyrone Esters from a Phomopsis sp. with Cytokine Production Inhibitory Activity.

A series of novel 6-substituted 5,6-dihydro-5-hydroxy-a-pyrone esters, 1 -3, isolated from fermentations of a Phomopsis sp. (Xenova culture collection no. X22502) have been identified as inhibitors of lipopolysaccharide (LPS)-induced cytokine production. These include the (66r)-4,6-dimethyldodecadien-2£',4JEI-dienoyl ester of phomalactone, 1, and two analogues bearing a prop-2J£'-enoic acid moiety at the 6-position of the a-pyrone ring. (65r)-4,6-Dimethyl2^,4^-dienoic acid, 4, and a hydroxylated analogue, 5, were also isolated and characterised. The most potent cytokine production inhibitor was 1, which inhibited LPS-induced tumour necrosis factor a (TNFa) production by U937 cells and LPS-induced interleukin 1/3 (IL-1/?) production by peripheral blood mononuclear cells (PBMC) with IC50 values of 80nM and 190nM respectively. The effect of 1 in PBMCwas selective for IL-1/3 relative to TNFa. The inhibition of IL-lj8 production by 1 involved a post-translational mechanism of action at the leyel of IL-1/3 secretion as demonstrated by the lack of an effect on cell-associated IL-1/? production. 1 showed no effect on the activity of caspase 1 in cytosolic extracts from the THP1 monocytic cell line.