Synthesis, hypoxia-selective cytotoxicity of new 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives

► We designed and synthesized a series of new 3-(alkoxymethylamino)-1,2,4-benzotriazine 1,4-dioxides 4a-r in high yields. ► All the compounds were synthesized through a convenient route and measured in vitro of hypoxic cytotoxicity and selectivity against 5 cancer cell lines. Some of them showed higher or similar cytotoxic activity and selectivity when compared to positive control TPZ. And preliminary SAR was concluded. ► Physico-chemical study as retention index was used to study the correlation between hypoxic activity and lipophilicity. ► Mechanism study using the potent derivatives 4b, 4l and 4m revealed that the cytotoxic activities of these compounds might be mediated by inducing apoptosis.