NF-κB is a transcription factor protein complex that plays an important role in some cancers and inflammatory responses. It can enhance the proliferation rate, reduce apoptosis, as well as create more blood flow to ensure the survival of cancer. Thus blocking the NF-κB pathway has potential therapeutic benefit. We designed a series of compounds based on quinazoline scaffold pharmacophore model which may have high binding affinity with p50 subunit of NF-κB. The compound series with phenyl substitution at position 2 of quinazoline proved to be more effective at inhibiting NF-κB function both theoretically and experimentally. These compounds also reduce the proliferation of numerous tumor cell lines and the mean GI50 for representative compound 2a is 2.88μM on NCI 60 cell lines. Compound 2a can induce significant apoptosis at the concentration of 1μM. The exploration of the mechanism of action of these compounds found that 2a does not inhibit kinases upstream of NF-κB and does not inhibit p65 translocation from the cytosol to the nucleus as 2b does. However 2a inhibits NF-κB dependent Luciferase expression as well as NF-κB target genes better than 2b. This may suggest that 2a inhibits the NF-κB pathway by directly blocking gene transcription, while 2b acts at cytoplasmic stage.
| Identifer | oai:union.ndltd.org:pacific.edu/oai:scholarlycommons.pacific.edu:uop_etds-1151 |
| Date | 01 January 2013 |
| Creators | Xu, Lu |
| Publisher | Scholarly Commons |
| Source Sets | University of the Pacific |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of the Pacific Theses and Dissertations |
| Rights | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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