Natural chalcones as dual inhibitors of HDACs and NF-κB

Histone deacetylase enzymes (HDACs) are emerging as a promising biologicaltarget for cancer and inflammation. Using a fluorescence assay, we tested thein vitro HDAC inhibitory activity of twenty-one natural chalcones, a widespreadgroup of natural products with well-known anti-inflammatory and antitumor effects.Since HDACs regulate the expression of the transcription factor NF-κB, we alsoevaluated the inhibitory potential of the compounds on NF-κB activation. Onlyfour chalcones, isoliquiritigenin (no. 10), butein (no. 12), homobutein (no. 15)and the glycoside marein (no. 21) showed HDAC inhibitory activity with IC50 valuesof 60-190 µM, whereas a number of compounds inhibited TNFα-induced NF-κB activationwith IC50 values in the range of 8-41 µM. Interestingly, three chalcones (nos. 10,12 and 15) inhibited both TNFα-induced NF-κB activity and total HDAC activityof classes I, II and IV. Molecular modeling and docking studies were performedto shed light into dual activity and to draw structure-activity relationshipsamong chalcones (nos. 1-21). To the best of our knowledge this is the first studythat provides evidence for HDACs as potential drug targets for natural chalcones.The dual inhibitory potential of the selected chalcones on NF-κB and HDACs wasinvestigated for the first time. This study demonstrates that chalcones can serveas lead compounds in the development of dual inhibitors against both targets inthe treatment of inflammation and cancer.