Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 28, Issue 19, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115669
Keywords
Thiapyran-pyrimidine; Anti-proliferation; EGFR inhibitor; Synthesis
Funding
- National Natural Science Foundation of China [21967009]
- Natural Science Foundation of Jiangxi, China [20181BBG70003, 20192BAB215061]
- Science and Technology Project Founded by the Education Department of Jiangxi Province, China [GJJ190583, GJJ180628]
- Youth Top Talent Support Program of Jiangxi Science & Technology Normal University [2019QNBJRC008]
- Nanchang Key Laboratory of Molecular Targeted Anticancer Drug Design and Evaluation [2019-NCZDSY-007]
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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 EGFR(T790M/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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