Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity

  • Qiang Feng
  • Hualong He
  • Tiantao Gao
  • Qiangsheng Zhang
  • Zhihao Liu
  • Xin Tao
  • Yongxia Zhu
  • Lidan ZhangEmail author
  • Luoting YuEmail author
Original Article


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.


EZH2 inhibitor Antiproliferation activity Benzomorpholine Structure–activity relationship 



We appreciate the funding support from the National Natural Science Foundation of China (No. 81602398) and the China Postdoctoral Science Foundation (Nos. 2015M582561, 2016T90861). We also thank Zhejiang Apeloa Medical Technology Co., Ltd, for financial support and Lihua Zhou of Key Laboratory of Biotherapy (Sichuan University) for NMR measurements.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Qiang Feng
    • 1
    • 2
  • Hualong He
    • 1
  • Tiantao Gao
    • 1
  • Qiangsheng Zhang
    • 1
  • Zhihao Liu
    • 1
  • Xin Tao
    • 1
  • Yongxia Zhu
    • 1
  • Lidan Zhang
    • 1
    Email author
  • Luoting Yu
    • 1
    Email author
  1. 1.Lab of Medicinal Chemistry, Cancer Center, West China HospitalSichuan University and Collaborative Innovation CenterChengduChina
  2. 2.College of Chemistry and Life ScienceChengdu Normal UniversityChengduChina

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