Study of the inhibitory effects on TNF-α-induced NF-κB activation of IMD0354 analogs

Abstract

Nuclear factor–κB (NF-κB) is an important nuclear transcription factor which regulates pro-inflammatory cytokines such as TNF-α, IL-6. Its role as immunoregulatory mediator makes it an attractive target in the development of treatments for inflammatory and autoimmune diseases. In this study, we synthesized derivatives of IMD0354, a known inhibitor for NF-κB, in attempt to understand the effect of benzanilide substitutions on its activity. The inhibition of these analogs on NF-κB activation was analyzed by luciferase assay. The inhibition of IKKβ phosphorylation and pro-inflammatory cytokines was determined by western blot and real-time PCR. The structure activity relationships showed that the hydroxyl group on IMD0354 is a critical moiety that resulting in the inhibition of NF-κB. Derivatives 1m, 2b and 2c were shown to inhibit proinflammatory cytokine production at low concentration. These newly synthesized compounds may be useful for the treatment of chronic inflammatory disorders or for cancer prevention.

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Derivatives of IMD035 were synthesized and few of them were found to inhibit NF-κB activation and reduced the proinflammatory cytokine TNF-α and IL-6 expression at low concentration. The structure activity relationships showed that the ortho hydroxyl group is an important moiety resulting in the inhibition. These compounds may be further developed into agents for the treatment of chronic inflammatory disorders or for cancer prevention.

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