Design, synthesis and antitumor activity of novel thiophene-pyrimidine derivatives as EGFR inhibitors overcoming T790M and L858R/T790M mutations

Abstract Five series of novel thiophene-pyrimidine derivatives (9a-h, 10a-f, 11a-f, 12a-f, 13a-f) have been synthesized and tested for their anti-proliferative activity against several cancer cell lines in which EGF is highly expressed. Most of the target compounds showed excellent activity against one or more cancer cell lines. The most promising compound 13a, of which IC50 values on of cell lines A549 and A431 (4.34 ± 0.60 μM and 3.79 ± 0.57 μM) were similar to the lead compound Olmutinib, showed strong activity and selectivity to EGFRT790M and EGFRT790M/L858R. Inhibition data of human normal hepatoma cell line LO2 indicated that most target compounds were less toxic to normal cells and had selective inhibitory effects on cancer cells. In addition, the structure-activity relationship was analyzed and the mechanism of apoptosis induced by the 13a was studied. The results showed that compound 13a induced late apoptosis of A431 cancer cells in a dose-dependent manner.