State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Bioorg Med Chem. 2011 Aug 15;19(16):5012-22. doi: 10.1016/j.bmc.2011.06.044. Epub 2011 Jun 21.
A novel type of cinnamic acid quinazoline amide derivatives (20-42), which designed the combination between quinazoline as the backbone and various substituted cinnamic acid as the side chain, have been synthesized and their biological activities were evaluated within cytotoxicity assay firstly and then potent EGFR inhibitory activity. Compound 42 demonstrated the most potent inhibitory activity (IC(50)=0.94 μM for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. Docking simulation was performed to position compound 42 into the EGFR active site to determine the probable binding model. Analysis of the binding conformation of 42 in active site displayed compound 42 was stabilized by hydrogen bonding interactions with Lys822, which was different from other derivatives. In the further study, Compounds 43 and 44 had been synthesized and their biological activities were also evaluated, which were the same as that we expected. Compound 43 has demonstrated significant EGFR (IC(50)=0.12 μM) and tumor growth inhibitory activity as a potential anticancer agent.
一种新型肉桂酸喹唑啉酰胺衍生物（20-42），它将喹唑啉作为骨干，将各种取代肉桂酸作为侧链进行设计，已经被合成，并在细胞毒性测定中首先评估了它们的生物活性，然后评估了它们对 EGFR 的抑制活性。化合物 42 表现出最强的抑制活性（对 EGFR 的 IC50=0.94μM），可在进一步的研究中作为潜在的 EGFR 抑制剂进行优化。进行了对接模拟，将化合物 42 定位到 EGFR 的活性部位，以确定可能的结合模型。对 42 在活性部位的结合构象进行分析显示，化合物 42 通过与 Lys822 的氢键相互作用得到稳定，这与其他衍生物不同。在进一步的研究中，合成了化合物 43 和 44，并对其生物活性进行了评估，结果与我们预期的一致。化合物 43 表现出显著的 EGFR（IC50=0.12μM）和肿瘤生长抑制活性，有望成为一种抗癌药物。
