Resorcylic
acid lactones are fungal metabolites that exhibit a wide range of
biological properties which includes oestrogenic, antifungal, phytotoxic and anti-inflammatory activity. The capacity of
5Z-7-oxo-zeaenol, a resorcylic
lactone of fungal origin and six naturally occurring analogues to inhibit
lipopolysaccharide (LPS)-induced
cytokine production in
phorbol 12-myristate-13-acetate (PMA)-treated cultured myelomonocytic cells (U937) was compared. The activity of the natural analogues in the U937 assay varied over 10(4)-fold, with
5Z-7-oxo-zeaenol the most potent of those tested inhibiting tumour
necrosis factor-alpha (
TNF alpha) production in these cells with IC50 of 6 nM. The isomeric 7-oxo-zeaenol and structurally more distant
monorden (
radicicol) were the next most active compounds with IC50 approximately 500 nM, and
zearalenone, the least active with IC50 > 400 microM.
5Z-7-oxo-zeaenol retained activity in LPS-stimulated peripheral blood mononuclear cells with an IC50 of 10-25 nM. This compound also inhibited LPS-induced
TNF alpha production in whole blood experiments (IC50 100-1000 nM) and lowered serum levels of
TNF alpha in mice when administered prior to LPS.
5Z-7-oxo-zeaenol was shown to inhibit the phosphorylation and activation of
mitogen-activated protein kinase (MAPK) induced by LPS. These data are consistent with a mechanism of action at or upstream of MAPK with resultant downstream effects. This series of naturally occurring analogues represents an interesting group of compounds with diverse
biological properties. Of this series, 5Z-7-oxo-zeanenol has exceptionally potent anti-inflammatory properties exhibited by its strong inhibition of
cytokine production.