Design, synthesis, and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives as potent antitumor agents

Two series of substituted thieno[3,2-d]pyrimidine derivatives as EZH2 inhibitors were synthesized via structural modifications of tazemetostat. The antiproliferative activity of compounds against SU-DHL-6, WSU-DLCL-2, K562, H358 and H1703 cancer cell lines and the toxicity against HEK293T cells were evaluated. The most promising compound 12e had a remarkable antitumor activity against SU-DHL-6, WSU-DLCL-2 and K562 cells (IC50 = 0.55 mu M, 0.95 mu M and 1.68 mu M, respectively) and low toxicity against HEK-293T cells (CC50 = 15.09 mu M). The preliminary structure-activity relationship (SAR) studies indicate that piperidine-2,6-dione was more suitable for a P1 moiety and benzyl-linked morpholine for a P5 moiety, which were beneficial for improving the antitumor activities. The biological evaluation showed that 12e can significantly affect lymphoma cell morphology, and induce the apoptosis of SU-DHL-6 cells in a concentration-dependent manner and inhibit their migration. These findings indicated that 12e would be an attractive chemical tool for the further optimization and evaluation of new EZH2 inhibitors.