Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity
Habens, F., Srinivasan, N., Oakley, F., Mann, D.A., Ganesan, A. and Packham, G. (2005) Novel sulfasalazine analogues with enhanced NF-kB inhibitory and apoptosis promoting activity. Apoptosis, 10, (3), 481-491. (doi:10.1007/s10495-005-1877-0).
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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.
|Keywords:||apoptosis, chronic lymphocytic leukaemia, fibrosis, hepatic stellate cell, NF-kB, sulfasalazine|
|Subjects:||Q Science > QD Chemistry
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Q Science > QR Microbiology
|Divisions:||University Structure - Pre August 2011 > School of Medicine > Cancer Sciences
University Structure - Pre August 2011 > School of Medicine > Infection, Inflammation and Repair
University Structure - Pre August 2011 > School of Chemistry
University Structure - Pre August 2011 > School of Medicine > Human Genetics
|Date Deposited:||26 Apr 2006|
|Last Modified:||27 Mar 2014 18:15|
|Contact Email Address:||G.K.Packham@soton.ac.uk|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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