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

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

  • Eur J Med Chem. 2020 Jan 1;185:111845. doi: 10.1016/j.ejmech.2019.111845.
Andrijana Meščić Macan 1 Nataša Perin 1 Silvio Jakopec 1 Marija Mioč 2 Marijana Radić Stojković 3 Marijeta Kralj 2 Marijana Hranjec 1 Silvana Raić-Malić 4
Affiliations

Affiliations

  • 1 University of Zagreb, Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20, HR-10000, Zagreb, Croatia.
  • 2 Ruđer Bošković Institute, Division of Molecular Medicine, Bijenička cesta 54, 10 000, Zagreb, Croatia.
  • 3 Ruđer Bošković Institute, Division of Organic Chemistry and Biochemistry, Bijenička cesta 54, 10 000, Zagreb, Croatia.
  • 4 University of Zagreb, Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20, HR-10000, Zagreb, Croatia. Electronic address: sraic@fkit.hr.
Abstract

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 if the 1,2,3-triazole moiety contains a short aliphatic side-chain. Thus, the chloropropyl side-chain in all three series had the highest impact on the 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 the submicromolar range. The compound 8a emerged as the most promising candidate because of its higher potency and some selectivity in the non-tumor aneuploid immortal keratinocyte (HaCaT) cells. Fluorescence and CD spectroscopy, as well as the thermal denaturation assays, revealed moderate to high DNA/RNA binding affinities of the selected compounds and identified intercalation as a dominant binding mode to both polynucleotides. However, results of intracellular distribution assay in human lung carcinoma (H460) cells suggest that both 8a and 8b do not target nuclear DNA and that their non-specific cytotoxic effect may be attributed to the damage of intercellular membranes.

Keywords

1,2,3-Triazoles; Antiproliferative activity; DNA/RNA binding; Fluorescent microscopy; benzimidazo[1,2-a]quinolines.

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