摘要/Abstract

细胞外信号相关激酶（ERK）是恶性肿瘤发生发展中的关键激酶，为了寻找新型结构的ERK抑制剂，采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物，其结构经¹H NMR、¹³C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明，大部分目标化合物对人结直肠癌细胞SW480和HCT-116具有中等强度的抑制作用，尤其是1-（4-氟苄基）-3-（5-（4-吗啉代苯基）吡啶-2-基）脲（18f）的IC₅₀分别达到0.36和0.55 μmol/L，对正常细胞L02毒性较低（>10 μmol/L）.同时，18f能抑制ERK的激酶活力（IC₅₀=0.051 μmol/L）和磷酸化水平，但不影响总ERK表达和上游丝裂原活化的细胞外信号调节激酶（MEK）的激活.上述结果为新型苄基吡啶基脲类ERK抑制剂的深入研究提供了重要参考信息.
关键词: 丝裂原活化蛋白激酶(MAPKs), 细胞外信号相关激酶(ERK), 二芳基脲, 合成, 抗肿瘤活性
Extracellular regulated protein kinase (ERK) is a key kinase in the development of cancer. 12 urea compounds containing morpholin rings were designed and synthesized in search of novel ERK inhibitors by using merging strategy. The structures of all compounds were confirmed by ¹H NMR, ¹³C NMR and HRMS. ERK kinase activity and cell proliferation test results indicate that most of the target compounds have moderately inhibitory effects on human colorectal cancer cells SW480 and HCT-116, especially the IC₅₀ of 1-(4-fluorobenzyl)-3-(5-(4-morpholinophenyl)pyridin-2-yl)urea (18f) reaches 0.36 and 0.55 μmol/L, respectively, and has low toxicity to normal cells L02 (>10 μmol/L). At the same time, 18f can inhibit ERK kinase activity (IC₅₀=0.051 μmol/L) and phosphorylation level, but does not affect total ERK expression and upstream upstream activation of mitogen-activated extracellular signal-regulated kinase (MEK) activation. These research provides important reference for the further study of novel benzylpyridylurea ERK inhibitors.
Key words: mitogen-activated protein kinases(MAPKs), extracellular regulated protein kinase (ERK), diarylurea, synthesis, antitumor activity


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