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[摘要]：To develop a more potent NF kappa B inhibitor from salicylic acid which is known to inhibit activity of NF kappa B, 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 NF kappa B 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 NF kappa B dependent luciferase and inducible nitric oxide synthase, a product of an NF kappa B target gene. Moreover, simultaneous amidation and chlorination of SA (5-chlorosalicylamide; 5-CSAM) conferred an additive NF kappa B 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 NF kappa B activity than other derivatives. Their IC(50)s' in the luciferase assay measured 15 mu M (5-CSPA), 17 mu M (5-CSPPA) and 91 mu M (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 NF kappa B plays a critical role in the pathogenic progresses. (C) 2011 Elsevier Masson SAS. All rights reserved. |
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