New [1,2,4]triazolo[4,3-c]quinazolines as intercalative Topo II inhibitors: Design, synthesis, biological evaluation, and in silico studies

Fifteen quinazoline derivatives were designed and synthesized as DNA intercalators. The cytotoxicity of the designed members was assessed against HCT-116 and HepG2 cancer cell lines. In addition, the topoisomerase II (Topo II) inhibitory effect was assessed. Compound 16 was the most cytotoxic and Topo II inhibitor with low cytotoxicity against Vero cells. Compounds 16, 17, and 18 showed significant DNA binding affinities. Compound 16 showed Topo II catalytic inhibitory effect at a concentration of 10 mu M. Further mechanistic investigations revealed the capability of compound 16 to induce apoptosis in HCT-116 cells and arrest the growth at the S and G2/M phases. Also, compound 16 showed a significant increase in the level of BAX (2.18-fold) and a marked decrease in the level of Bcl-2 (1.9-fold) compared to the control cells. In silico studies revealed the ability of the synthesized members to bind to the DNA-Topo II complex.

Automated summary

Fifteen derivatives of quinazoline were synthesized as DNA intercalators, and their cytotoxicity against HCT-116 and HepG2 cancer cell lines as well as their inhibitory effect on Topo II were evaluated. Compound 16 exhibited the highest cytotoxicity and Topo II inhibition, but had low cytotoxicity against Vero cells. Compounds 16, 17, and 18 showed significant DNA binding affinities. Compound 16 also displayed Topo II catalytic inhibitory effect at a concentration of 10 mu M. Further investigations revealed that compound 16 induced apoptosis in HCT-116 cells and arrested growth at the S and G2/M phases, accompanied by increased BAX level and decreased Bcl-2 level compared to control cells. In silico studies demonstrated the ability of the synthesized derivatives to bind to the DNA-Topo II complex.