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

Abstract

In a screening for new inhibitors of NF-κB 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-κB and AP-1 mediated SEAP expression with an IC50 of 1 ~ 2 μg/ml (4.2 ~ 8.4 μM) and 3 ~ 5 μg/ml (12.6 ~ 21 μM) respectively. 1-Hydroxy-2-hydroxymethyl-3-pent-1-enyibenzene (2) inhibits the TPA-induced NF-κB and AP-1 mediated SEAP expression with an IC50 of 7 μg/ml (36.4 μM) and 5 μg/ml (26 μM). 3 showed only a weak inhibition of the AP-1 and no influence on NF-κB dependent reporter gene expression. In COS-7 and HeLa S3 cells electrophoretic mobility shift assays showed that cycloepoxydon strongly reduced the TPA and TNF-α mediated binding of NF-κB to a high affinity consensus sequence which was due to the inhibition of phosphorylation of the inhibitory protein IκB.