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 approximately 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 alpha-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 LPS-induced tumour necrosis factor alpha (TNFalpha) production by U937 cells and LPS-induced interleukin 1beta (IL-1beta) production by peripheral blood mononuclear cells (PBMC) with IC50 values of 80 nM and 190 nM respectively. The effect of 1 in PBMC was selective for IL-1beta relative to TNFalpha. The inhibition of IL-1beta production by 1 involved a post-translational mechanism of action at the level of IL-1beta secretion as demonstrated by the lack of an effect on cell-associated IL-1beta production. 1 showed no effect on the activity of caspase 1 in cytosolic extracts from the THP1 monocytic cell line.
Wrigley
S K
SK
TerraGen Discovery, UK.
Sadeghi
R
R
Bahl
S
S
Whiting
A J
AJ
Ainsworth
A M
AM
Martin
S M
SM
Katzer
W
W
Ford
R
R
Kau
D A
DA
Robinson
N
N
Hayes
M A
MA
Elcock
C
C
Mander
T
T
Moore
M
M
D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005285:Fermentation; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011753:Pyrones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D020298:U937 Cells / Q000187:drug effects* / Q000378:metabolism
D004952:Esters; D007375:Interleukin-1; D007783:Lactones; D008070:Lipopolysaccharides; D011753:Pyrones; D014409:Tumor Necrosis Factor-alpha