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-enylbenzene (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.