State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
J Med Chem. 2013 Jun 13;56(11):4738-48. doi: 10.1021/jm400463q. Epub 2013 May 24.
A series of hybrids (12a-k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 μM) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50 values of 0.007 and 0.029 μM, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-κB activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.
一系列（苯磺酰基）呋喃酮和氨嘧啶的杂化物（12a-k）被合成并作为表皮生长因子受体（EGFR）抑制剂进行了生物评价，用于干预非小细胞肺癌（NSCLC）。化合物 12k 表现出强烈且选择性的 EGFR L858R/T790M 抑制活性（IC50=0.047 μM），并对 EGFR 突变 NSCLC 细胞系 HCC827（del E746_A750）和 H1975（L858R/T790M）显示出抗增殖作用，IC50 值分别为 0.007 和 0.029 μM。此外，12k 在 H1975 细胞中释放高水平的 NO，但在正常人类细胞中没有，并且其活性在使用 NO 清除剂预处理时被减弱。此外，12k 比 WZ4002（1）更强烈地诱导 H1975 和 HCC827 细胞凋亡，抑制 H1975 细胞中的 EGFR 下游信号传导，并抑制 H1975 细胞中的核因子-κB 激活，而 1 在相同条件下没有显著影响。最后，12k 显著抑制了 H1975 异种移植小鼠模型中的肿瘤生长。总的来说，12k 可能是治疗 NSCLC 的有前途的候选药物。
