Synthesis, characterization and in vitro cytotoxicity of ruthenium(II) metronidazole complexes: Cell cycle arrest at G1/S transition and apoptosis induction in MCF-7 cells

Abstract

Ruthenium compounds are known to be potential drug candidates since they offer the potential for reduced toxicity. Furthermore, the various oxidation states, different mechanisms of action and ligand substitution kinetics give them advantages over platinum-based complexes, making them suitable for use in biological applications. So, herein, novel ruthenium(II) complexes with metronidazole as ligand were obtained [RuCl(MTNZ)(dppb)(4,4'-Mebipy)]PF₆ (1), [RuCl(MTNZ)(dppb)(4,4'-Methoxybipy)]PF₆ (2), [RuCl(MTNZ)(dppb)(bipy)]PF₆ (3) and [RuCl(MTNZ)(dppb)(phen)]PF₆ (4) where, MTNZ = metronidazole, dppb = 1,4-bis(diphenylphosphino)butane, 4,4'-Mebipy = 4,4'-dimethyl-2,2'-bipyridine, 4,4'-Methoxybipy = 4,4'-dimethoxy-2,2'-bipyridine, bipy = 2,2'-bipyridine and phen = 1,10-phenanthroline. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV-Vis spectroscopy, cyclic voltammetry, ³¹P{¹H}, ¹H, ¹³C{¹H} and Dept 135 NMR and mass spectrometry. The interaction of complexes 1-4 with DNA was evaluated, and their cytotoxicity profiles were determined on four different tumor cell lines derived from human cancers (SK-MEL-147, melanoma; HepG2, hepatocarcinoma; MCF-7, estrogen-positive breast cancer; A549, non-small cell lung cancer). We demonstrated that complexes (1) and (3) are promising antitumor agents once inhibited the proliferative behavior of MCF-7 cells and induced apoptosis.

Keywords: Antitumor activity; Metronidazole; Ruthenium complexes.