CYCLOEPOXYDON, 1-HYDROXY-2-HYDROXYMETHYL-3-PENT-1-ENYLBENZENE AND -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 sign al transduction pathways in COS-7 cells using secreted alkaline phosph atase (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 ferment ations of the deuteromycete strain 45-93. Cycloepoxydon inhibits the T PA-induced NF-kappa B and AP-1 mediated SEAP expression with an IC50 o f 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-hydroxymet hyl-3-pent-1-enylbenzene (2) inhibits the TPA-induced NF-kappa B and A P-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 t he inhibition of phosphorylation of the inhibitory protein I kappa B.