New manganese(II), iron(II), cobalt(II), nickel(II) and copper(II) saccharinate complexes of 2,6-bis(2-benzimidazolyl)pyridine as potential anticancer agents

Eur J Med Chem. 2020 Sep 15:202:112535. doi: 10.1016/j.ejmech.2020.112535. Epub 2020 Jul 3.

Abstract

New mononuclear complexes [Mn(NO3)(sac)(H2O)(bzimpy)]·2DMF (Mn), [Fe(sac)2(H2O)(bzimpy)]·2H2O (Fe), [Co(bzimpy)2](sac)2·2H2O (Co), [Ni(bzimpy)2](sac)2·H2O·i-PrOH (Ni) and [Cu(sac)2(bzimpy)]·3DMF (Cu) (sac = saccharinate and bzimpy = 2,6-bis(2-benzimidazolyl)pyridine) were synthesized and structurally characterized by elemental analysis, UV-Vis, IR, ESI-MS and X-ray diffraction. The anticancer activity of the metal complexes against A549 (lung), MCF-7 (breast), HT29 (colon) cancer cells and MCF10A (normal human breast epithelial) cells was tested and compared with those of cisplatin and bzimpy. The complexes displayed potent cytotoxic activity especially in MCF-7 and A549 cell lines, but they were practically inactive against the normal cells. Mechanistic studies with Mn and Cu complexes on A549 cells indicated that the complexes induced G0/G1 arrest. Both complexes increased intracellular ROS (reactive oxygen species) levels and successfully caused both mitochondrial dysfunction and double-strand DNA breaks. The up-regulated Bax and down-regulated Bcl-2 expression levels, caspase-3/7 activation and reduced Fas expression indicated that Mn and Cu induced ROS-dependent mitochondria-mediated intrinsic apoptosis in A549 cells.

Keywords: 2,6-Bis(2-benzimidazolyl)pyridine; Anticancer activity; Apoptosis; First row divalent transition metals; Saccharinate.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Metals, Heavy / chemistry
  • Metals, Heavy / pharmacology*
  • Molecular Structure
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Saccharin / analogs & derivatives
  • Saccharin / chemistry
  • Saccharin / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • 2,6-bis(benzimidazol-2-yl)pyridine
  • Antineoplastic Agents
  • Benzimidazoles
  • Coordination Complexes
  • Metals, Heavy
  • Pyridines
  • Saccharin