Natural chalcones as dual inhibitors of HDACs and NF-κB

Abstract

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.

Antioxidant properties of several coumarin–chalcone hybrids from theoretical insights

“…In compound 5 the introduction of an electron donor group -OH at position C8 and an electron withdrawing group -Br at C6 contributes to red shi the transition. With the exception of 7 all the other newly systems (6,(8)(9)(10)) that contain several substituents show signicant red shis.…”

Naturally occurring chalcones and their biological activities

“…Isoliquiritigenin (11), butein (45) and homobutein (49) have been reported to inhibit not only histone deacetylase activity but TNF-a induced NF-jB activity as well. SAR studies showed that hydroxy groups at the 2 0 -, 4 0 -, 3-and 4-positions were important for dual activity of the compounds (Orlikova et al 2012).…”

Characterization of the Fluorescence Properties of 4‐Dialkylaminochalcones and Investigation of the Cytotoxic Mechanism of Chalcones

“…Sharp structure–activity relationships (SAR) have been observed, suggesting a well‐defined interaction between chalcones and the responsible cellular target for cytotoxicity . A number of putative targets have been proposed, including tubulin , several kinases , cathepsins , topoisomerases , MDM2 , and many others . However, data to date are far from sufficient to suggest any direct interactions of chalcones with these targets in cells.…”