engleski

Synthesis, antiproliferative activity and DNA/RNA-binding properties of mono- and bis-(1,2,3-triazolyl)-appended benzimidazo[1,2-a]quinoline derivatives

The three series of 5-mono- and 2, 5-bis-1, 2, 3-triazolyl-substituted benzimidazo[1, 2-a]quinolines as potential antitumor agents were synthesized. Their growth-inhibitory activity is influenced by the introduction of fluorine at C-2 and the mono-triazolyl nuclei at C-5 of the tetracyclic skeleton, particularly containing short aliphatic side chain. Thus, chloropropyl side chain in all three series had the highest impact on inhibitory effect. 1, 2, 3-Triazolyl−2-fluorobenzimidazo[1, 2-a]quinoline conjugates 8a and 8b with 3-chloropropyl and 2-hydroxyethyl substituents, respectively, exhibited the most pronounced cytostatic effect on colon cancer (HCT116) cells in submicromolar range. The compound 8a emerged as the most promising candidate because of its higher potency and some selectivity in non- tumor HaCaT cells. Fluorescence and CD spectroscopy, as well as thermal denaturation assays revealed moderate to high DNA/RNA binding affinities of selected compounds, and identified intercalation, as a dominant binding mode to both polynucleotides. However, intracellular distribution assay in H460 cells showed that none of the evaluated compounds enters the nucleus, suggesting that they do not target nuclear DNA, as a potential mechanism of action.

antiproliferative activity ; DNA/RNA binding ; benzimidazo[1 ; 2-a]quinolines ; 1, 2, 3-triazoles ; fluorescent microscopy

nije evidentirano