title: Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity.
abstract: The NF-kB transcription factor plays a key role in the regulation of apoptosis by modulating expression of a wide range of cell death control molecules. NF-kB also plays an important role in human diseases by promoting inappropriate cell survival. Small molecule inhibitors of NF-kB are therefore likely to provide novel therapeutic opportunities. Sulfasalazine (SFZ) is a synthetic anti-inflammatory comprising an aminosalicylate, 5-amino salicylic acid (5-ASA), linked to an antibiotic, sulfapyridine (SPY). SFZ, but not 5-ASA or SPY, inhibits activation of NF-kB. We synthesised a small number of SFZ analogues and determined their ability to inhibit NF-kB activity and promote apoptosis in chronic lymphocytic leukaemia and hepatic stellate cells, where NF-kB plays an important role in cell survival. Remarkably, 3 of the 6 analogues synthesised were significantly more effective (up to 8-fold) inhibitors of NF-kB dependent transcription and this increased activity was associated with enhanced apoptosis. Therefore, it is possible to readily improve the NF-kB inhibiting activity of SFZ and analogues of SFZ may be attractive therapeutic agents for malignancies and chronic liver disease where NF-kB is thought to play a significant role.
authors.affiliation: Cancer Research UK Oncology Unit, Cancer Sciences Division, School of Medicine, Southampton General Hospital, University of Southampton, SO16 6YD, UK.
authors.forename: F
authors.initials: F
authors.lastname: Habens
authors.forename: N
authors.initials: N
authors.lastname: Srinivasan
authors.forename: F
authors.initials: F
authors.lastname: Oakley
authors.forename: D A
authors.initials: DA
authors.lastname: Mann
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.forename: G
authors.initials: G
authors.lastname: Packham
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D004854:Herpesvirus 4, Human; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000503:physiopathology; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D051381:Rats; D012460:Sulfasalazine / Q000031:analogs & derivatives*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha; D012460:Sulfasalazine