Structureeactivity relationship of salicylic acid derivatives on inhibition of TNF-a dependent NFkB activity: Implication on anti-inflammatory effect of N-(5-chlorosalicyloyl)phenethylamine against experimental colitis

摘要

To develop a more potent NFkB inhibitor from salicylic acid which is known to inhibit activity of NFkB, a transcription factor regulating genes involved in immunity, inflammation and tumorigenesis, derivatives of salicylic acid (SA) where the 5 position, carboxyl or hydroxyl group was modified were treated in HCT116 cells transfected with an NFkB dependent luciferase gene and LPS-stimulated RAW264.7 cells. Amidation of the carboxylic group or substitution of chlorine at the 5 position increased the ability of SA to suppress the expression of NFkB dependent luciferase and inducible nitric oxide synthase, a product of an NFkB target gene. Moreover, simultaneous amidation and chlorination of SA (5-chlorosalicylamide; 5-CSAM) conferred an additive NFkB inhibitory activity on SA. To further enhance the inhibitory activity, N-modification was imposed on 5-CSAM N-(5-chlorosalicyloyl)phenethylamine (5-CSPA), N-(5-chlorosalicyloyl)3-phenylpropylamine (5-CSPPA) and N-(5-chlorosalicyloyl)4-hydroxyphenylethylamine (5-CSHPA) showed greater potencies for inhibiting NFkB activity than other derivatives. Their IC50s' in the luciferase assay measured 15 mM (5-CSPA), 17 mM (5-CSPPA) and 91 mM (5-CSHPA). Rectal administration of 5-CSPA ameliorated TNBS-induced rat colitis, which was more effective than a conventional drug, 5-aminosalicylic acid. These data may provide useful information for development of a therapeutic agent for treatment of diseases where NFkB plays a critical role in the pathogenic progresses.