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