Design, synthesis and biological evaluation of novel 2,4-bismorpholinothieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives as potent antitumor agents

Abstract

To develop novel therapeutic agents with anticancer activities, two series of novel 2,4-bismorpholinyl-thieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives were designed, synthesized and evaluated for their biological activities. Among them, compound A₁₂ showed the most potent antitumor activities against HCT116, PC-3, MCF-7, A549 and MDA-MB-231 cell lines with IC₅₀ values of 3.24 μM, 14.37 μM, 7.39 μM, 7.10 μM, and 16.85 μM, respectively. Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound A₁₂. The results showed that compound A₁₂ obviously inhibited the proliferation of A549 cell lines and decreased mitochondrial membrane potential, which led to the apoptosis of cancer cells and suppressed the migration of tumor cells.

Keywords: Antiproliferative activities; PI3Kα; Synthesis; Thieno[3,2-d]pyrimidine.