Design, synthesis and biological evaluation of novel 2,4-diaminopyrimidine derivatives as potent antitumor agents

Abstract

For developing novel therapeutic agents with anticancer activities, two series of novel 2,4-diaminopyrimidine derivatives possessing triazolopiperazine or 1,4,8-triazaspiro[4.5]decan-3-one scaffolds were designed and synthesized. Preliminary investigations showed that some compounds exhibited moderate to excellent potency against four tested cancer cell lines as compared with palbociclib and momelotinib. In particular, the most promising compounds 9k and 13f showed the most potent antitumor activities with IC₅₀ values of 2.14/1.98 μM, 3.59/2.78 μM, 5.52/4.27 μM, and 3.69/4.01 μM against A549, HCT-116, PC-3 and MCF-7 cell lines, respectively. Structure–activity relationship (SAR) studies were conducted based on the variation of the moiety of the aromatic ring and the terminal aniline on the pyrimidine core. Furthermore, the mechanism of their anticancer activity was clarified by further exploring the bioactivity. The results showed that compound 9k obviously inhibited the proliferation of A549 cell lines, induced a great decrease in the mitochondrial membrane potential leading to apoptosis of cancer cells, suppressed the migration of tumor cells and prolonged the A549 cell cycle distribution, representing blockage at the G2-M phase and accumulation at the S phase.