2. Academic Validation
  3. Discovery of thiapyran-pyrimidine derivatives as potential EGFR inhibitors

Discovery of thiapyran-pyrimidine derivatives as potential EGFR inhibitors

  • Bioorg Med Chem. 2020 Oct 1;28(19):115669. doi: 10.1016/j.bmc.2020.115669.
Zhen Xiao 1,  Cilong Chu 1,  Lingjia Zhou 1,  Zhihui Zhou 1,  Qian Zhang 1,  Feiyi Yang 1,  Zunhua Yang 2,  Pengwu Zheng 1,  Shan Xu 3,  Wufu Zhu 4
Affiliations

Affiliations

  • 1 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China.
  • 2 College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, China.
  • 3 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. Electronic address: shanxu9891@126.com.
  • 4 Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi 330013, China. Electronic address: zhuwufu-1122@163.com.
PMID: 32912435 DOI: 10.1016/j.bmc.2020.115669
Abstract

A series of novel thiapyran-pyrimidine derivatives (10a-10h, 11a-11g, 12a-12f, 13a-13f, 14a-14f) were synthesized and their antiproliferative activities were tested. Most of the target compounds showed good activity on one or more Cancer cell lines but low activity on human normal cell LO2. The most promising compound 13a exhibited the similar IC50 values on A549 and H1975 cell lines to the lead drug Olmutinib, and exhibited excellent activity and selectivity on EGFRT790M/L858R in the kinase experiment. AO and Hoechst33258 staining indicated that 13a could effectively induce H1975 cells Apoptosis. Cell cycle and Apoptosis analysis suggested that 13a could block Cancer cells in G2/M phase and induce into late Apoptosis in a manner of concentration-dependent. The structure-activity relationship of 13a was analyzed to explore its mechanism. All the results showed that 13a was a promising EGFR inhibitor.

Keywords

Anti-proliferation; EGFR inhibitor; Synthesis; Thiapyran-pyrimidine.

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