Two out of Three Musketeers Fight against Cancer: Synthesis, Physicochemical, and Biological Properties of Phosphino CuI, RuII, IrIII Complexes

Abstract

Two novel phosphine ligands, Ph2PCH2N(CH2CH3)3 (1) and Ph2PCH2N(CH2CH2CH2CH3)2 (2), and six new metal (Cu(I), Ir(III) and Ru(II)) complexes with those ligands: iridium(III) complexes: Ir(η5-Cp*)Cl2(1) (1a), Ir(η5-Cp*)Cl2(2) (2a) (Cp*: Pentamethylcyclopentadienyl); ruthenium(II) complexes: Ru(η6-p-cymene)Cl2(1) (1b), Ru(η6-p-cymene)Cl2(2) (2b) and copper(I) complexes: [Cu(CH3CN)2(1)BF4] (1c), [Cu(CH3CN)2(2)BF4] (2c) were synthesized and characterized using elemental analysis, NMR spectroscopy, and ESI-MS spectrometry. Copper(I) complexes turned out to be highly unstable in the presence of atmospheric oxygen in contrast to ruthenium(II) and iridium(III) complexes. The studied Ru(II) and Ir(III) complexes exhibited promising cytotoxicity towards cancer cells in vitro with IC50 values significantly lower than that of the reference drug—cisplatin. Confocal microscopy analysis showed that Ru(II) and Ir(III) complexes effectively accumulate inside A549 cells with localization in cytoplasm and nuclei. A precise cytometric analysis provided clear evidence for the predominance of apoptosis in induced cell death. Furthermore, the complexes presumably induce the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. Gel electrophoresis experiments revealed that Ru(II) and Ir(III) inorganic compounds showed their unusual low genotoxicity towards plasmid DNA. Additionally, metal complexes were able to generate reactive oxygen species as a result of redox processes, proved by gel electrophoresis and cyclic voltamperometry. In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated. It was proven that the hydrocarbon chain elongation of the phosphine ligand coordinated to the metal ions does not influence the cytotoxic effect of resulting complexes in contrast to metal ions type.

Synthesis, physicochemical characterization and antiproliferative activity of phosphino Ru(ii) and Ir(iii) complexes

“…8 Furthermore, it has been shown that organometallic halfsandwich Ru(II) and Ir(III) complexes exhibit excellent in vitro and in vivo anticancer properties, but still need to be explored in detail. [17][18][19][20][21] Hence, ruthenium-based antitumor complexes represent a promising alternative to platinum drugs, a number of them being already in clinical trials. 22,23 Ruthenium has a large range of available oxidation states under physiological conditions.…”

New N4-Donor Ligands as Supramolecular Guests for DNA and RNA: Synthesis, Structural Characterization, In Silico, Spectrophotometric and Antimicrobial Studies

“…In fact, Cu(II) complexes are a promising group of bioactive agents exhibiting anticancer, antimicrobial, and anti-inflammatory properties, to cite only a few [ 18 ]. Cu(I) coordination compounds, despite the oxidative instability of the ions [ 19 ], have been studied as potential antitumor [ 20 ] and antimicrobial agents as well [ 16 , 17 ]. For instance, in 2022, Villarreal et al presented the synthesis, structural, and biological studies of a new Cu(I) complex that was shown to be a potential antimalarial drug [ 21 ].…”