Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity
Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity
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新型 EZH2 抑制剂苯并吗啉衍生物的合成及生物学评价，用于抗非小细胞肺癌活性
DOI：
10.1007/s11030-018-9903-7
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发表时间：
2019-08-01
影响因子：
3.8
通讯作者：
Yu, Luoting
中科院分区：
文献类型：
--
作者：
Feng, Qiang;He, Hualong;Yu, Luoting
据报道，组蛋白赖氨酸甲基转移酶EZH2在肿瘤侵袭性、转移和不良预后中起重要作用。本研究合成了一系列苯并噻吩啉衍生物，并对其作为EZH2抑制剂进行了生物学评价。以3-氨基-5-溴-2-羟基苯甲酸为原料，经过环化、铃木偶联和酰胺化等步骤，得到了收率较高的目标化合物。初步优化研究发现了几种有效的新型EZH2抑制剂（6b, 6c， 6x和6y）。6y对A549和NCI-H1975细胞株有抑制作用（IC50分别为1.1 μ M和1.1 μ M）。进一步的研究表明，6y可以降低完整细胞中EZH2的表达，并导致细胞在G2/M期停滞。
The histone lysine methyltransferase EZH2 has been reported to play important roles in cancer aggressiveness, metastasis and poor prognosis. In this study, a series of benzomorpholine derivatives were synthesized and biologically evaluated as EZH2 inhibitors. The target compounds were obtained in good yields from 3-amino-5-bromo-2-hydroxybenzoic acid via cyclization, Suzuki coupling and amidation as the key steps. A preliminary optimization study led to the discovery of several potent novel EZH2 inhibitors (6b, 6c, 6x and 6y). Moreover, 6y inhibited the A549 and NCI-H1975 cell lines (IC50 = 1.1 mu M and 1.1 mu M, respectively). Further studies indicated that 6y can reduce EZH2 expression in intact cells and cause cell arrest in the G2/M phase.