Synthesis, antiproliferative activity and DNA binding properties of novel 5-Aminobenzimidazo[1,2-a]quinoline-6-carbonitriles

•5-Aminobenzimidazo[1,2-a]quinolines with prominent antiproliferative activity.•Compounds 9, 19 and 20 bind to DNA as strong intercalators.•Compounds 9 and 19 enter the cell according to cellular distribution.•Compound 9 efficiently targets the nucleus whereas 19 is mostly cytoplasmic.

The synthesis of 5-amino substituted benzimidazo[1,2-a]quinolines prepared by microwave assisted amination from halogeno substituted precursor was described. The majority of compounds were active at micromolar concentrations against colon, lung and breast carcinoma cell lines in vitro. The N,N-dimethylaminopropyl 9 and piperazinyl substituted derivative 19 showed the most pronounced activity towards all of the three tested tumor cell lines, which could be correlated to the presence of another N heteroatom and its potential interactions with biological targets. The DNA binding studies, consisting of UV/Visible absorbency, melting temperature studies, and fluorescence and circular dichroism titrations, revealed that compounds 9, 19 and 20 bind to DNA as strong intercalators. The cellular distribution analysis, based on compounds’ intrinsic fluorescence, showed that compound 20 does not enter the cell, while compounds 9 and 19 do, which is in agreement with their cytotoxic effects. Compound 9 efficiently targets the nucleus whereas 19, which also showed DNA intercalating properties in vitro, was mostly localised in the cytoplasm suggesting that the antitumor mechanism of action is DNA-independent.

Graphical abstractEvaluation of the mechanism of action of 5-amino substituted benzimidazo[1,2-a]quinolines revealed binding of strong DNA intercalators. N,N-dimethylaminopropyl substituted intercalator entered the cell localize in the nucleus.Figure optionsDownload full-size imageDownload as PowerPoint slide