Bicyclic Cyclohexenones as Inhibitors of NF-κB Signaling

A series of structurally simplified cryptocaryone analogues were synthesized by a facile Pd-catalyzed acetoxylation of alkyne-tethered cyclohexadienones and evaluated as inhibitors of NF-κB signaling. Compounds 10 and 11 were found to possess low micromolar inhibitory properties toward induced NF-κB activity by blocking p50/p65 nuclear protein through a covalent inhibition mechanism. Both compounds were able to inhibit NF-κB-induced IL-8 expression and exhibited antiproliferative activity against two model cancer cell lines. These analogues constitute a promising new scaffold for the development of novel NF-κB inhibitors and anticancer agents.