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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Acknowledgements
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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Feng, Q., He, H., Gao, T. et al. Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity. Mol Divers 23, 681–696 (2019). https://doi.org/10.1007/s11030-018-9903-7
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DOI: https://doi.org/10.1007/s11030-018-9903-7