Cytotoxic Activity, Apoptosis Induction and Structure–Activity Relationship of 2‐Phenylphthalazin‐2‐ium Salts as Promising Antitumor Agents

Abstract

Inspired by sanguinarine and chelerythrine, various 2‐phenylphthalazin‐2‐ium salts as simple analogues were designed according to the structure of natural products. On the basis of previous research, this study evaluated the inhibition activity of these compounds on tumor cells, apoptosis induction as well as their structure‐activity relationship (SAR). The results indicated that the compounds showed IC50 values of 1.21–14.77 μM against NB4 cells and 4.68–17.44 μM against MKN‐45 cells, respectively, superior to positive control cis‐platinum with IC50 values of 2.39 and 11.36 μM or their model compound chelerythrine with IC50 values of 1.49 and 12.70 μM. Acridine orange/ethidium bromide and ultrastructure observation of cells suggested that these compounds could induce apoptosis of tumor cells. Meanwhile, 2‐(3,4‐Dichlorophenyl)phthalazin‐2‐ium Bromide‐induced apoptosis was dependent on the excessive formation of ROS and amplified by the mitochondrial pathway. The preliminary SAR indicated that substitution pattern on the N‐aromatic ring remarkably influenced the cytotoxicity of the compounds. The trend showed that the presence of electron‐donating groups caused a significant improvement of the cytotoxicity. And in many cases that the 3’ site was the most advantageous substitution position for the enhancement of the cytotoxicity. Hence, the results demonstrated that the title compounds werea class of potential compounds for the development of novel antitumor drugs.