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

• Published in: Journal of inorganic biochemistry Vol. 237; p. 112022
• Main Authors: Candido, Caio Cesar, Silva, Henrique Vieira Reis, Zavan, Bruno, Ionta, Marisa, Barbosa, Marília Imaculada Frazão, Doriguetto, Antônio Carlos
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2022
• Subjects: 2,2'-Dipyridyl - chemistry; Antineoplastic Agents - chemistry; Antitumor activity; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Coordination Complexes - chemistry; Humans; Ligands; Lung Neoplasms; MCF-7 Cells; Metronidazole; Ruthenium - chemistry; Ruthenium complexes; Antitumor activity; Ruthenium complexes; Metronidazole
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2022.112022

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.
Chemistry of new ruthenium metronidazole complexes was examined. At least two new promising antitumor agents were obtained. The complexes inhibited the proliferative behavior of MCF-7 and induced apoptosis. [Display omitted]
•Synthesis and characterization of ruthenium(II) metronidazole complexes•Ruthenium(II) metronidazole complexes as antitumor drug candidates•Cytotoxicity profiles and DNA interaction study•Inhibition of the proliferative behavior of estrogen-positive breast carcinoma cells•Ru(II)-complexes exhibit a high DNA-binding affinity.