Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-kappa B Inhibitors

For many inflammatory diseases, new effective drugs with fewer side effects are needed. While it appears promising to target the activation of the central pro-inflammatory transcription factor NF-kappa B, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quinazoline derivatives were developed that selectively inhibit the activation of NF-kappa B in macrophage-like THP-1 cells while showing low general cytotoxicity. One of the best compounds, 19, strongly inhibited the production of IL-6 (IC50 = 0.84 mu M) and, less potently, of TNF alpha (IC50 = 4.0 mu M); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC(50)s of 1.1 and 11.4 mu M, respectively. Interestingly, 19 was found to block the translocation of the NF-kappa B dimer to the nucleus, although its release from the I kappa B complex was unaffected. Furthermore, 19 suppressed the phosphorylation of NF-kappa B-p65 at Ser468 but not at Ser536; however, 19 did not inhibit any kinase involved in NF-kappa B activation. The only partial suppression of p65 phosphorylation might be associated with fewer side effects. Since several compounds selectively induced cell death in activated macrophage-like THP-1 cells, they might be particularly effective in various inflammatory diseases that are exacerbated by excess activated macrophages, such as arteriosclerosis and autoimmune diseases.