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 (6
S)-4, 6-dimethyldodecadien-2
E, 4
E-dienoyl ester of phomalactone,
1, and two analogues bearing a prop-2
E-enoic acid moiety at the 6-position of the α-pyrone ring. (6
S)-4, 6-Dimethyl-2
E, 4
E-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 IC
50 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.
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