Rational design, synthesis and biological evaluation of novel 2-(substituted amino)-[1,2,4]triazolo[1,5-a]pyrimidines as novel tubulin polymerization inhibitors

作者：Chen, Lin; Ji, Tang-Yang; Huo, Xian-Sen; Zeng, Zhi-Yu; Ye, Wei-Xuan; Dai, Chen-Chen; Zhang, Yu-Qi; You, Wen-Wei; Zhao, Pei-Liang^*

来源：European Journal of Medicinal Chemistry, 2022, 244: 114864.

DOI：10.1016/j.ejmech.2022.114864

• 2-Arylamino-[1
• 2
• 4]triazolo[1
• 5-a]pyrimidine
• Anticancer agents
• Tubulin inhibitors

Following our previously reported compound 3, we designed and synthesized a series of new 2-(substituted amino)-[1,2,4]triazolo[1,5-a]pyrimidines as potential tubulin polymerization inhibitors. Among them, analogue 4k, having a 3-hydroxy-4-methoxyphenylamino group, was observed to display excellent antiproliferative ac-tivity toward HeLa, HCT116, A549, and T47D with the IC50 values of 0.31, 1.28, 3.99 and 10.32 mu M, respec-tively, which were approximately 32, 48, 4, and 5-fold improvement compared with 3. Importantly, 4k possessed significant selectivity in inhibiting cancer cell lines over the normal HEK293 cells. Moreover, futher mechanism analysis demonstrated that 4k caused G2/M arrest, induced cells apoptosis in HeLa cells, and manifested sig-nificant tubulin polymerization inhibitory activity with the IC50 value of 4.9 mu M, which is comparable to CA-4 (IC50 = 4.2 mu M). The observations performed in this study reveal that 2-arylamino- [1,2,4]triazolo[1,5-a]py-rimidines represent a novel class of tubulin polymerization inhibitors with potent antiproliferative efficacy.

• 单位
  南方医科大学