We describe the synthesis and biological activity of a new class of 1,3-diaryltriazenes, namely 4-nitro-substituted 1,3-diaryltriazenes. Structure-activity relationship analysis reveals that 1,3-diaryltriazenes can be modified from inactive to highly cytotoxic compounds by the introduction of two nitro groups at the para positions of benzene rings and two additional electron-withdrawing groups (bromo, chloro, trifluoromethyl or fluoro substituents) at their ortho position. In order to increase the solubility of the modified compounds, we introduced various acyl groups to their triazene nitrogen. The results of LC-MS/MS analysis showed that N-acyltriazenes can be considered as prodrugs of non-acylated triazenes. Selected 3-acetyl-1,3-bis(2-chloro-4-nitrophenyl)-1-triazene (8b) is highly cytotoxic against different tumor cell lines, including cisplatin-resistant laryngeal carcinoma cells. Notably, its antiproliferative activity is significantly higher against tumor cells than against normal cells. DNA binding analysis suggests that neither 8b nor its non-acylated derivative 8a bind into the minor groove of DNA. Instead, 8b induces reactive oxygen species that could provoke endoplasmic reticulum (ER(a)) stress finally leading to apoptosis. Our data suggest that 4-nitro-substituted 1,3-diaryltriazenes are a new class of anticancer molecules which preferentially target malignant cells and may serve as potential antitumor agents.
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