Dinuclear ruthenium(II) polypyridyl complexes: Mechanistic study with biomolecules, DNA/BSA interactions and cytotoxic activity. (1st March 2020)

• Record Type: Journal Article
• Authors: Medjedović, Milica; Simović, Ana Rilak; Ćoćić, Dušan; Milutinović, Milan; Senft, Laura; Blagojević, Stefan; Milivojević, Nevena; Petrović, Biljana
• Is Part Of: Polyhedron. Volume 178(2020)
• Publication Date: 2020-03-01
• Subjects: Bpy 2, 2′-bipyridine -- phen 1, 10-phenantroline -- pzn pyrazine -- 5′-GMP guanosine-5′-monophosphate -- l-Met l-methionine -- GSH glutathione -- DNA deoxyribonucleic acid -- PBS phosphate-buffered saline -- EB ethidium bromide -- Hoechst 33258 2-(4-hydroxyphenyl)-5-[5-(4-methylpipera-zine-1-yl)benzimidazo-2-yl]-benzimidazole -- MDA-MB-231 human breast cancer cell -- HCT-116 human colorectal cancer cell -- tpy 2, 2′:6′, 2″-terpyridine -- Cl-tpy 4′-chloro-2, 2′:6′, 2″-terpyridine -- Cl-Ph-tpy 4′-(4-chlorophenyl)-2, 2′:6′, 2″-terpyridine -- en 1, 2-diaminoethane -- dach 1, 2-diaminocyclohexane -- o-bqdi o-benzoquinonediimine -- CT-DNA calf thymus DNA -- HT DNA herring testes DNA -- HSA human serum albumin -- mtefc (2-(methylthio)ethyl)ferrocene -- mtpfc (3-(methylthio)propyl)ferrocene) -- Hepes buffer N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid -- DMSO dimethylsulfoxide -- MVD Molegro Virtual Docker -- DMEM Dulbecco's Modified Eagle Medium -- MTT 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide -- 9-MeG 9-methylguanine -- l-His l-histidine -- Pz pyrazole -- Tz 1, 2, 4-triazole -- Py pyridine -- NAMI-A imidazolium trans-[tetrachlorido(1H-imidazole)(dimethylsulfoxide)ruthenate(III)] -- 4-azo 4, 4″-azobis(2, 2′-bipyridine); Dinuclear Ru(II) complexes -- Polypyridyl -- DNA -- BSA -- Cytotoxicity; Chemistry, Inorganic -- Periodicals; Chimie inorganique -- Périodiques; Organometaalverbindingen; Anorganische chemie; 546.05
• DOI: 10.1016/j.poly.2019.114334
• Languages: English
• ISSNs: 0277-5387

Abstract

Graphical abstract: This study confirmed that biomolecules, such as amino acids, peptides, nucleotides, DNA and proteins, might be the suitable biological targets for dinuclear pyrazine-bridged Ru(II) complexes. The dinuclear Ru(II) complexes showed moderate cytotoxic activity against MDA-MB-231 breast cancer cells, suggesting their cytotoxic selectivity against various types of cancer cells and potential antimetastatic activity. Highlights: Interactions of dinuclear pyrazine-bridged Ru(II) complexes with biomolecules. The kinetic and mechanistic studies form an essential part of the study. Dinuclear Ru(II) complexes showed good binding affinity toward DNA and BSA. Molecular docking studies on DNA and BSA. Evaluation of cytotoxic activity on HCT-116 and MDA-MB-231 cancer cell lines. Abstract: The substitution reactions of dinuclear Ru(II) polypyridyl complexes, i.e. [{RuCl(bpy)2 }2 (μ-pzn)][PF6 ]2 (1 ) and [{RuCl(phen)2 }2 (μ-pzn)][PF6 ]2 (2 ) (bpy = 2, 2′-bipyridine, phen = 1, 10-phenanthroline, μ-pzn = pyrazine), with mononucleotide guanosine-5′-monophosphate (5′-GMP) and sulfur-containing nucleophiles, such as l -methionine (l -Met) and glutathione (GSH) were studied by UV–Vis spectroscopy. The structures of dinuclear Ru(II) complexes 1 and 2 were preserved during the substitution processes and the calculated enthalpies and entropies of activation (ΔH ≠ > 0, ΔS ≠ < 0) supported an associative mechanism of substitution. The DNA binding affinity of complexes 1 and 2 was evaluated by UV–Vis, fluorescence emission spectroscopy and by viscosity measurements in aqueous phosphate buffer solution (PBS) at pH 7.40. Additionally, competitive binding reactions with an intercalative agent ethidium bromide (EB) and the known minor groove binder Hoechst 33258 were studied as well. The obtained results indicate that complexes 1 and 2 can interact with DNA through the intercalation and/or minor groove binding, where the latest was preferred. This observation is in a good agreement with the results obtained by molecular docking. Furthermore, both complexes strongly quenched the fluorescence of tryptophan residues in serum albumin (BSA) through both static and dynamic quenching ( K sv = 10 4 –10 5 M −1 ). In addition, complexes 1 and 2 showed moderate cytotoxic activity against human breast cancer cells (MDA-MB-231), while both were inactive against human colorectal cancer cells (HCT-116).