Cycloepoxydon

Nuclear factor (NF)-kappaB is a transcription factor that induces the immunoglobulin kappa chain, cytokines such as interleukin (IL)-1, IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-alpha and interferon gamma, and cell adhesion proteins. It also induces anti-apoptotic proteins, and inhibits TNF-alpha and anticancer drug-induced apoptosis. Therefore, NF-kappaB function inhibitors may be useful as anti-inflammatory and anticancer agents. Microbial products such as panepoxydone, cycloepoxydon and gliotoxin are known to inhibit activation of NF-kappaB. We have designed and synthesized new NF-kappaB inhibitors from the structure of an antibiotic, epoxyquinomicin C. The designed compound, DHM2EQ, inhibited TNF-alpha-induced activation of NF-kappaB and showed a therapeutic effect in mouse rheumatoid arthritis model.

An enantioselective total synthesis of the novel, biologically active epoxyquinone natural product (-)-cycloepoxydon has been accomplished from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone. A new cycloepoxydon related heptacyclic dimer has been prepared and characterized. [reaction: see text]

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.