Issue 46, 2023

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

Abstract

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 μM, 0.95 μM and 1.68 μM, respectively) and low toxicity against HEK-293T cells (CC50 = 15.09 μM). 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.

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

Supplementary files

Article information

Article type
Paper
Submitted
31 Jul 2023
Accepted
24 Oct 2023
First published
10 Nov 2023

New J. Chem., 2023,47, 21318-21331

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

Y. Zhang, J. Shen, J. Li, Z. Wang, Y. Wang, Y. Zhu, S. Ding, Y. Zhou, Y. Chen and J. Liu, New J. Chem., 2023, 47, 21318 DOI: 10.1039/D3NJ03576J

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