Synthesis, characterization and biological evaluation of novel Ru(II)–arene complexes containing intercalating ligands

Abstract

Three new ruthenium(II)-arene complexes, namely [(η(6)-p-cymene)Ru(Me2dppz)Cl]PF6 (1), [(η(6)-benzene)Ru(Me2dppz)Cl]PF6 (2) and [(η(6)-p-cymene)Ru(aip)Cl]PF6 (3) (Me2dppz=11,12-dimethyldipyrido[3,2-a:2',3'-c]phenazine; aip=2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying η(6)-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me2dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin.

Ruthenium(ii) p-cymene complexes of a benzimidazole-based ligand capable of VEGFR2 inhibition: hydrolysis, reactivity and cytotoxicity studies

“…35,36 In our case, the difference is caspase 8 activation for 1-3, in comparison to caspase 7; this suggests that the complexes may operate through multiple pathways initially, but after caspase 8 activation, they follow the mitochondriamediated intrinsic pathway of apoptosis. 35,68,69 For earlier reported Ru(II) p-cymene benzimidazole-based complexes where detailed mechanistic studies have been explored in the literature, most studies suggest that DNA binding is the major cause of cell death through cell cycle arrest, mostly in G2/M phase 28,29,47,48 and S phase. 43,47 These Ru(II) complexes are known to inhibit cyclin-dependent kinases (cdk1/cdk2) 28,44 and downregulate ribosomal proteins (RPS21) and cytokines, such as β-actin.…”

“…35,68,69 For earlier reported Ru(II) p-cymene benzimidazole-based complexes where detailed mechanistic studies have been explored in the literature, most studies suggest that DNA binding is the major cause of cell death through cell cycle arrest, mostly in G2/M phase 28,29,47,48 and S phase. 43,47 These Ru(II) complexes are known to inhibit cyclin-dependent kinases (cdk1/cdk2) 28,44 and downregulate ribosomal proteins (RPS21) and cytokines, such as β-actin. 70 However, for complexes 1-3, the model nucleobase studies using 9-EtG and the DNA binding studies suggest that DNA binding is not the major pathway of action.…”

“…42 Ru(II) p-cymene complexes of benzimidazole-containing ligands are active anti-cancer agents. 28,29,[43][44][45][46][47][48] However, the detailed mechanism of action has been probed for only a few Ru(II) p-cymene complexes bearing benzimidazole ligands. 28,[48][49][50][51] The well-characterized complexes (1)(2)(3) were studied for their hydrolytic behaviour, the effects of their halides, and their reactivities in the presence and absence of glutathione.…”

DNA-Binding and Anticancer Activity of Binuclear Gold(I) Alkynyl Complexes with a Phenanthrenyl Bridging Ligand

“…Ligands such as the π-delocalized planar polypyridyls (e.g., diphenylphenazine) have afforded moderate-to-strong DNA-intercalating complexes [15,16]. Modified acetylacetonato [17], amine [18,19], arene [20][21][22], and Schiff base [23,24] ligands have also been used in DNA-binding complex construction. In the pursuit of efficient DNA binders, one well-known strategy is to use a polycyclic aromatic fragment in the ligand that has been designed to form π-π interactions with specific units in the DNA [25,26].…”

Biological evaluation of rare earth complexes bearing 1H‐imidazo[4,5‐f]‐1,10‐phenanthroline moiety as promising anticancer chemotherapeutics

“…In the research of metal‐based anticancer drugs, aside from the significance of the central metal, the choice of ligand plays an important role as well . Complexes with 1 H ‐imidazo[4,5‐f]‐1,10‐phenanthroline moieties are able to express a few meaningful properties in the medicinal area . The DNA binding and anticancer activity of Ru(II) complexes with 2‐(4‐(diethoxymethyl)‐1 H ‐imidazo[4,5‐ f ]‐1,10‐phenanthroline) have been thoroughly studied .…”