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-KB 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-hydroxymethyl-3-pent-1,3-dienylbenzene (3) were isolated from fermentations of the deuteromycete strain 45-93. Cycloepoxydon inhibits the TPA-induced NF-KB and AP-1 mediated SEAP expression with an IC50 of 1-2 micrograms/ml (4.2-8.4 microns) and 3-5 micrograms/ml (12.6-21 microns) respectively. 1-Hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene (2) inhibits the TPA-induced NF-KB and AP-1 mediated SEAP expression with an IC50 of 7 micrograms/ml (36.4 microns) and 5 micrograms/ml (26 microns). 3 showed only a weak inhibition of the AP-1 and no influence on NF-KB 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-KB to a high affinity consensus sequence which was due to the inhibition of phosphorylation of the protein IKB.
Gehrt
A
A
Lehrbereich Biotechnolgie, Universitaät, Kaiserslautern, Germany.
Erkel
G
G
Anke
T
T
Sterner
O
O
D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D006224:Cricetinae; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
C113320:1-hydroxy-2-hydroxymethyl-3-pent-1,3-dienylbenzene; C113319:1-hydroxy-2-hydroxymethyl-3-pent-1-enylbenzene; D000475:Alkenes; D004852:Epoxy Compounds; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D018808:Transcription Factor AP-1; C113318:cycloepoxydon