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-alpha-pyrone esters, 1 similar to 3, isolated from fermentations of a Phomopsis sp. (Xenova cult ure collection no. X22502) have been identified as inhibitors of lipopolysa ccharide (LPS)-induced cytokine production. These include the (6S)-4,6-dime thyldodecadien-2E,4E-dienoyl ester of phomalactone, 1, and two analogues be aring a prop-2E-enoic acid moiety at the 6-position of the alpha-pyrone rin g. (6S)-4,6-Dimethyl-2E,4E-dienoic acid 4, and a hydroxylated analogue, 5, were also isolated and characterised. The most potent cytokine production i nhibitor was 1, which inhibited LPS-induced tumour necrosis factor alpha (T NF alpha) production by U937 cells and LPS-induccd interleukin 1 beta (IL-1 beta) production by peripheral blood mononuclear cells (PBMC) with IC50 va lues of 80 nM and 190 nM respectively. The effect of 1 in PBMC was selectiv e for IL-1 beta relative to TNF alpha. The inhibition of IL-1 beta producti on by 1 involved a post-translational mechanism of action at the level of I L-1 beta secretion as demonstrated by the lack of an effect on cell-associa ted IL-1 beta production. I showed no effect on the activity of caspase 1 i n cytosolic extracts from the THP1 monocytic cell line.