Biological approach of anticancer activity of new benzimidazole derivatives

A series of new benzimidazole derivatives, earlier synthesized, was tested in vitro as new bioreductive prodrugs with the potential anticancer activity. Their effect on the DNA destruction and growth inhibition into selected tumor cell lines at normoxia and hypoxia conditions was determined.

The human lung adenocarcinoma A549 cell line was used to determine the anticancer activity of the analyzed compounds by using WST-1 assay. The apoptosis test (caspase 3/7 assay) was used to define the cytotoxic way of tumor cells death. Additionally test In situ DNA Damage Assay Kit was applied to recognize the DNA destruction.

Four of the examined compounds (1, 3, 7, 9) show a very good antiproliferative effect and three of them are specific for hypoxia conditions (2, 4, 8).

Compound 8 is the most cytotoxic against human lung adenocarcinoma A549 cells at hypoxic conditions. Hypoxia/normoxia cytotoxic coefficient of compound 8 (4.75) is close to hypoxia/normoxia cytotoxic coefficient of tirapazamine (5.59) - reference substance in our experiments and this parameter locates it between mitomycin C and 2-nitroimidazole (misonidazole). The screening test of the caspase-dependent apoptosis proved that the exposure of compounds 1-2 and 7-8 against A549 cells for a 48 h promote apoptotic cell death. Additionally, the test of the DNA damage established that compounds 1, 2, 7, 8 are specific agents for the hypoxia-selective cytotoxicity of nitrobenzimidazoles [6,26].