Discovery of thiapyran-pyrimidine derivatives as potential EGFR inhibitors |
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| Affiliation: | 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;1. National Engineering Research Center for Manufacturing Technology of TCM Solid Preparation, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China;2. College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China;3. College of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, China;4. College of Pharmacy, Jilin Medical University, Jilin 132013, China;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt;1. Department of Food and Drug, University of Parma, Parma, Italy;2. Department of Medicine and Surgery, University of Parma, Parma, Italy |
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| 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. |
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| Keywords: | Thiapyran-pyrimidine Anti-proliferation EGFR inhibitor Synthesis |
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