A novel (6S)-4,6-dimethyldodeca-2E,4E-dienoyl ester of phomalactone and related alpha-pyrone esters from a Phomopsis sp. with cytokine production inhibitory activity.

A series of novel 6-substituted 5, 6-dihydro-5-hydroxy-α-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 (6S)-4, 6-dimethyldodecadien-2E, 4E-dienoyl ester of phomalactone, 1, and two analogues bearing a prop-2E-enoic acid moiety at the 6-position of the α-pyrone ring. (6S)-4, 6-Dimethyl-2E, 4E-dienoic acid, 4, and a hydroxylated analogue, 5, were also isolated and characterised. The most potent cytokine production inhibitor was 1, which inhibited EPS-induced tumour necrosis factor α (TNFα) production by U937 cells and EPS-induced interleukin 1β (IL-1β) production by peripheral blood mononuclear cells (PBMC) with IC50 values of 80 nM and 190nM respectively. The effect of 1 in PBMC was selective for IL-1β relative to TNFα. The inhibition of IL-1β production by 1 involved a post-translational mechanism of action at the leyel of IL-1β secretion as demonstrated by the lack of an effect on cell-associated IE-1β production. 1 showed no effect on the activity of caspase 1 in cytosolic extracts from the THP1 monocytic cell line.