New quinoline-arylamidine hybrids: Synthesis, DNA/RNA binding and antitumor activity

Eur J Med Chem. 2017 Sep 8:137:196-210. doi: 10.1016/j.ejmech.2017.05.054. Epub 2017 May 28.

Abstract

Four series of new hybrid molecules with 7-chloroquinoline and arylamidine moieties joined through the rigid -O- (groups I (2a-g) and II (5a-g)) or flexible -NH-CH2-CH2-O- (groups III (8a-g) and IV (10a-g)) linker were synthesized, and their DNA/RNA binding properties and cytotoxic activity were tested, against several human cancer lines. The compounds and their interaction with DNA and RNA were studied by UV-Vis and CD spectroscopy. The obtained results showed that the binding affinity of the investigated compounds increases proportionally with the increase of the length and number of groups able to form hydrogen bonds with ds-polynucleotides. Improvement of binding was additionally achieved by reduction of the structural rigidity of the investigated compounds, new hybrid compounds preferentially bind to ctDNA. For most of them the DNA/RNA grooves are dominant binding sites, except for the compounds from group II for which intercalation in polyA-polyU was the dominant binding mode. The antiproliferative effects were tested by the MTT test on normal (MDCK1), carcinoma (HeLa and CaCo2) and leukemia cell lines (Raji and K462). The GI50 values for all investigated compounds ranged from 5 to more than 100 × 10-6 mol dm-3. Carcinoma cells were more resistant to the investigated compounds than leukemia cells. The most effective compounds against leukemia cell lines were from group IV (10a-g), with GI50 values ranging from of 5 and 35 × 10-6 mol dm-3. The cell cycle arrest was investigated by flow cytometry and the obtained results indicate that the selected compounds, 2d, 2e, 8a, 10d, 10e, and 10f, induce changes in the cell cycle of treated cells, but the cycle phase distribution varies between them. A significant decrease in the number of cells in S phase (p < 0.001) was observed in all treated cells, but only 10d and 10f induce cell cycle arrest at G0/G1 phase, dominantly.

Keywords: 7-Chloroquinoline; Antitumor activity; Aromatic amidine; DNA/RNA binding; Hybrid molecule.

MeSH terms

  • Amidines / chemistry
  • Amidines / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding Sites / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • DNA, Neoplasm / antagonists & inhibitors*
  • DNA, Neoplasm / chemistry
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • RNA, Neoplasm / antagonists & inhibitors*
  • RNA, Neoplasm / chemistry
  • Structure-Activity Relationship

Substances

  • Amidines
  • Antineoplastic Agents
  • DNA, Neoplasm
  • Quinolines
  • RNA, Neoplasm
  • quinoline