Discovery of Novel Small-Molecule Inhibitors of NF-κB Signaling with Antiinflammatory and Anticancer Properties

Abstract

Excessive NF-κB activation contributes to the pathogenesis of numerous diseases. Small-molecule inhibitors of NF-κB signaling have significant therapeutic potential especially in treating inflammatory diseases and cancers. In this study, we performed a cell-based high-throughput screening to discover novel agents capable of inhibiting NF-κB signaling. On the basis of two hit scaffolds from the screening, we synthesized 69 derivatives to optimize the potency for inhibition of NF-κB activation, leading to successful discovery of the most potent compound Z9j with over 170-fold enhancement of inhibitory activity. Preliminary mechanistic studies revealed that Z9j inhibited NF-κB signaling via suppression of Src/Syk, PI3K/Akt, and IKK/IκB pathways. This novel compound also demonstrated antiinflammatory and anticancer activities, warranting its further development as a potential multifunctional agent to treat inflammatory diseases and cancers.

Cytotoxicity Assay of 2,4-Dihydroxide-4’-Methoxychalcone Against Cervical (HeLa) Cancer Cell by MTT Assay

“…Investigated of chalcone, particularly that hydroxyl group in the aromatic ring did not give a significant activity (Zhang et al, 2018), but unsaturated carbonyl of chalcone predicted inhibiting the activity of transcription activity in an uncontrolled cell (Bazzaro et al, 2011) From Scheme 2, unsaturated carbonyl of chalcone attacked by Ik-kB, that it was IKK protein-mediated of the NF-kB activation pathway (Yadav et al, 2011). Based on the mechanism reaction of Scheme 2, bonding between protein Ik-kB and unsaturated carbonyl of chalcone may stop NF-kB pathway as caused proliferation of cancer cells in humans.…”

Crystal structure and anti-inflammatory activity of (3E,5E)-1-((4-chlorophenyl)sulfonyl)-3-(pyridin-4-ylmethylene)-5-(2-(trifluoromethyl)benzylidene)piperidin-4-one, C25H18ClF3N2O3S

“…For title compound, the expression rate of NO production could reach 52.19 ± 0.37%. The result showed that title compound displayed potential inhibitory effect on LPS-induced NO secretion than PDTC [8,16,17].…”

Crystal structure and anti-inflammatory activity of (3E,5E)-3,5-bis(2-fluorobenzylidene)-1-((4-fluorophenyl)sulfonyl)piperidin-4-one, C25H18F3NO3S

“…Based on literatures, the pro-inflammatory cytokines, such as NO, TNF-α and IL-6 can trigger inflammation resulting in various diseases. If the secretion of these pro-inflammatory cytokines can be effectively suppressed, it can play a role in inhibiting inflammation [16,17]. In this study, the effect of the title compound on NO production in mouse RAW264.7 cells induced by LPS was examined by ELISA.…”