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

Automated summary

A series of new compounds were designed and synthesized as potential tubulin polymerization inhibitors, among which one compound showed excellent antiproliferative activity and selectivity against cancer cells, as well as significant tubulin polymerization inhibitory activity.