Synthesis and biological evaluation of 4-nitro-substituted 1,3-diaryltriazenes as a novel class
of potent antitumor agents
M. Osmak1 ,T. Čimbora-Zovko1, A. Brozovic1, I. Piantanida1, G. Fritz2, A. Virag3, B. Alič3,
V. Majce3, M. Kočevar3 and S. Polanc3
1
Rudjer Boskovic Institute, Zagreb, Croatia; 2University Medicinal Center of the Johannes
Gutenberg University Mainz, Mainz, Germany; 3Faculty of Chemistry and Chemical
Technology, University of Ljubljana, Ljubljana, Slovenia
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 1,3diaryltriazenes 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-acetyl1,3-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 (ERa) 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.
*PCT patent application is pending for this invention.