Natural chalcones as dual inhibitors of HDACs and NF-κB.
Histone deacetylase enzymes (HDACs) are emerging as a promising biological             target for cancer and inflammation. Using a fluorescence assay, we tested the             in vitro HDAC inhibitory activity of twenty-one natural chalcones, a widespread             group of natural products with well-known anti-inflammatory and antitumor effects.             Since HDACs regulate the expression of the transcription factor NF-κB, we also             evaluated the inhibitory potential of the compounds on NF-κB activation. Only             four chalcones, isoliquiritigenin (no. 10), butein (no. 12), homobutein (no. 15)             and the glycoside marein (no. 21) showed HDAC inhibitory activity with IC50 values             of 60-190 µM, whereas a number of compounds inhibited TNFα-induced NF-κB activation             with 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 activity             of classes I, II and IV. Molecular modeling and docking studies were performed             to shed light into dual activity and to draw structure-activity relationships             among chalcones (nos. 1-21). To the best of our knowledge this is the first study             that provides evidence for HDACs as potential drug targets for natural chalcones.             The dual inhibitory potential of the selected chalcones on NF-κB and HDACs was             investigated for the first time. This study demonstrates that chalcones can serve             as lead compounds in the development of dual inhibitors against both targets in             the treatment of inflammation and cancer.
Laboratory of Molecular and Cellular Biology of Cancer, Cancer                     and Blood Research Foundation, Kirchberg Hospital, Luxembourg, Luxembourg.
B
B
Orlikova
M
M
Schnekenburger
M
M
Zloh
F
F
Golais
M
M
Diederich
D
D
Tasdemir
D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008958:Models, Molecular; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D047188:Chalcones; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D012097:Repressor Proteins; D049410:Luciferases, Renilla; C409470:HDAC8 protein, human; D006655:Histone Deacetylases