A novel [1,2,4] triazolo [1,5-a] pyrimidine-based phenyl-linked steroid dimer: Synthesis and its cytotoxic activity

•Compound 3 was efficiently synthesized in two steps.•Compound 3 exhibited broad-spectrum cytotoxic activity and was more potent than 5-Fu.•Compound 3 showed low toxicity against L-02.•Compound 3 showed cell cycle arrest at G2/M phase and induced apoptosis.

A novel [1,2,4] triazolo [1,5-a] pyrimidine-based phenyl-linked steroid dimer was designed, synthesized and evaluated for its cytotoxic activity against five human cancer cell lines and the cytotoxicity against human normal liver cell L-02. Compound 3 showed excellent cytotoxic activity and good selectivity between cancer and normal cells. Further mechanistic studies revealed that treatment of EC109 cells with compound 3 caused an obvious G2/M arrest in a concentration- and time-dependent manner and induced apoptosis probably through the mitochondrial pathway accompanied with the decrease of mitochondrial membrane potential, activations of caspase-9/-3, cleavage of MDM2 as well as up-regulation of the expressions of p53 and Bax.

Graphical abstractCompound 3 showed excellent cytotoxic activity against five human cancer cell lines (IC50 < 3.2 μM) and low toxicity against L-02 and induced G2/M arrest and apoptosis probably through the mitochondrial pathway.Figure optionsDownload full-size imageDownload as PowerPoint slide