title: Structure-activity relationship of salicylic acid derivatives on inhibition of TNF-α dependent NFκB activity: Implication on anti-inflammatory effect of N-(5-chlorosalicyloyl)phenethylamine against experimental colitis.
abstract: To develop a more potent NFκB inhibitor from salicylic acid which is known to inhibit activity of NFκB, 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 NFκB 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 NFκB dependent luciferase and inducible nitric oxide synthase, a product of an NFκB target gene. Moreover, simultaneous amidation and chlorination of SA (5-chlorosalicylamide; 5-CSAM) conferred an additive NFκB 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 NFκB activity than other derivatives. Their IC(50)s' in the luciferase assay measured 15μM (5-CSPA), 17μM (5-CSPPA) and 91μM (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 NFκB plays a critical role in the pathogenic progresses.
authors.affiliation: Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: Sookjin
authors.initials: S
authors.lastname: Kang
authors.forename: Sungchae
authors.initials: S
authors.lastname: Hong
authors.forename: Soowhan
authors.initials: S
authors.lastname: Yum
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D054426:Chemokine CXCL2 / Q000032:analysis / Q000378:metabolism; D003092:Colitis / Q000188:drug therapy*; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D012459:Salicylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054426:Chemokine CXCL2; C513296:Cxcl2 protein, rat; D016328:NF-kappa B; D012459:Salicylates; D014409:Tumor Necrosis Factor-alpha