Cycloepoxydon, 1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene and 1-hydroxy-2-hydroxymethyl-3-pent-1,3-dienylbenzene, new inhibitors of eukaryotic signal transduction

In a screening for new inhibitors of NF-kappa B and AP-1 mediated signal transduction pathways in COS-7 cells using secreted alkaline phosphatase (SEAP) as a reporter gene three novel compounds, cycloepoxydon (1), 1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene (2) and 1-hydroxy-2-hydroxymethyl-3-pent-1,3-dienylbenzene (3) were isolated from fermentations of the deuteromycete strain 45-93. Cycloepoxydon inhibits the TPA-induced NF-kappa B and AP-1 mediated SEAP expression with an IC50 of 1 similar to 2 mu g/ml (4.2 similar to 8.4 mu M) and 3 similar to 5 mu g/ml (12.6 similar to 21 mu M) respectively. 1-Hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene (2) inhibits the TPA-induced NF-kappa B and AP-1 mediated SEAP expression with an IC50 of 7 mu g/ml (36.4 mu M) and 5 mu g/ml (26 mu M). 3 showed only a weak inhibition of the AP-1 and no influence on NF-kappa B dependent reporter gene expression. In COS-7 and HeLa S3 cells electrophoretic mobility shift assays showed that cycloepoxydon strongly reduced the TPA and TNF-alpha mediated binding of NF-kappa B to a high affinity consensus sequence which was due to the inhibition of phosphorylation of the inhibitory protein I kappa B.