Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity |
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Authors: | Feng Qiang He Hualong Gao Tiantao Zhang Qiangsheng Liu Zhihao Tao Xin Zhu Yongxia Zhang Lidan Yu Luoting |
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Institution: | 1.Lab of Medicinal Chemistry, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China ;2.College of Chemistry and Life Science, Chengdu Normal University, Chengdu, China ; |
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Abstract: |
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 µM and 1.1 µM, respectively). Further studies indicated that 6y can reduce EZH2 expression in intact cells and cause cell arrest in the G2/M phase.
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