Department of Pharmaceutics and Medicinal Chemistry, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA.
Bioorg Med Chem. 2013 Jan 15;21(2):540-6. doi: 10.1016/j.bmc.2012.10.051. Epub 2012 Nov 15.
NF-kB is a transcription factor protein complex that can be found in almost all animal cell types and is a key player in some cancers and inflammatory responses. It can enhance the proliferation rate, reduce apoptosis, as well as creating more blood flow to ensure the survival of cancer, thus blocking the NF-kB pathway has potential therapeutic benefit. We designed a series of compounds based on a quinazoline scaffold pharmacophore model which may have high binding affinity with the p50 subunit of NF-kB. The compound series with phenyl substitution at the 2 position of the quinazoline proved to be more effective at inhibiting NF-kB function both theoretically and experimentally. These compounds also reduce the proliferation of numerous tumor cell lines and the mean GI(50) for compound 2a is 2.88 μM against the NCI-60 cell line. At the same time, compound 2a can induce significant apoptosis in EKVX cell line at the concentration of 1 μM.
NF-κB 是一种转录因子蛋白复合物，几乎存在于所有动物细胞类型中，是一些癌症和炎症反应的关键参与者。它可以提高增殖率，减少细胞凋亡，并产生更多的血流以确保癌症的存活，因此阻断 NF-κB 途径具有潜在的治疗益处。我们设计了一系列基于喹唑啉骨架药效团模型的化合物，这些化合物可能与 NF-κB 的 p50 亚基具有高结合亲和力。喹唑啉 2 位带有苯基取代的化合物系列在理论和实验上都被证明对抑制 NF-κB 功能更有效。这些化合物还能抑制多种肿瘤细胞系的增殖，化合物 2a 对 NCI-60 细胞系的平均 GI（50）为 2.88 μM。同时，化合物 2a 在 1 μM 的浓度下能诱导 EKVX 细胞系产生显著的细胞凋亡。
