Studies on gambogic acid (IV): Exploring structure-activity relationship with IκB kinase-beta (IKKβ)

Previously we have reported a series of gambogic acid's analogs and have identified a compound that possessed comparable in vitro growth inhibitory effect as gambogic acid. However, their target protein as well as the key pharmacophoric motifs on the target have not been identified yet. Herein we report that gambogic acid and its analogs inhibit the activity of I kappa B Kinase-beta (IKK beta) through suppressing the activation of TNF alpha/NF-kappa B pathway, which in turn induces A549 and U251 cell apoptosis. IKK beta can serve as one of gambogic acid's targets. The preparation of the compounds was carefully discussed in the article. Caged 4-oxa-tricyclo[4.3.1.0(3,7)]dec-2-one xanthone, which was identified as the pharmacophoric scaffold, represents a promising therapeutic agent for cancer and useful probe against NF-kappa B pathway. (C) 2012 Elsevier Masson SAS. All rights reserved.