title: 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.
abstract: 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.
authors.affiliation: TerraGen Discovery, UK.
authors.forename: S K
authors.initials: SK
authors.lastname: Wrigley
authors.forename: R
authors.initials: R
authors.lastname: Sadeghi
authors.forename: S
authors.initials: S
authors.lastname: Bahl
authors.forename: A J
authors.initials: AJ
authors.lastname: Whiting
authors.forename: A M
authors.initials: AM
authors.lastname: Ainsworth
authors.forename: S M
authors.initials: SM
authors.lastname: Martin
authors.forename: W
authors.initials: W
authors.lastname: Katzer
authors.forename: R
authors.initials: R
authors.lastname: Ford
authors.forename: D A
authors.initials: DA
authors.lastname: Kau
authors.forename: N
authors.initials: N
authors.lastname: Robinson
authors.forename: M A
authors.initials: MA
authors.lastname: Hayes
authors.forename: C
authors.initials: C
authors.lastname: Elcock
authors.forename: T
authors.initials: T
authors.lastname: Mander
authors.forename: M
authors.initials: M
authors.lastname: Moore
mesh_terms: 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
chemical_list: D004952:Esters; D007375:Interleukin-1; D007783:Lactones; D008070:Lipopolysaccharides; D011753:Pyrones; D014409:Tumor Necrosis Factor-alpha