Interaction of methotrexate, an anticancer agent, with copper(II) ions : coordination pattern, DNA-cleaving properties and cytotoxic studies

The acid–base properties and the Cu(II) binding processes of methotrexate (MTX) were characterized by selected spectroscopic techniques and potentiometric measurements. The pH titration data showed that MTX behaves as a triprotic ligand. The deprotonation constants were determined for α-COOH and γ-COOH groups and (N1)H+ from the pteridine ring. Taking all the obtained results into consideration, a coordination pattern was proposed. The DNA-cleaving activity and reactive oxygen species (ROS) generation were investigated for both MTX and the Cu(II)–MTX system. The complex displayed a promising nuclease activity toward plasmid DNA in the presence of hydrogen peroxide. Interestingly, the induction of ROS, such as hydroxyl radicals, superoxide anions or singlet oxygen, was excluded and a different mechanism of DNA degradation was proposed. As MTX is now commonly used in anticancer therapy i.e. against lung cancer, basic cell-based studies were carried out to establish if its Cu(II) complex exhibits higher cytotoxic properties than the ligand alone. Activities of both compounds were also tested against colon carcinoma. Moreover, the determined values of IC50 were confronted with the cytotoxic activity of cisplatin

Copper(II) complexes with 2-ethylpyridine and related hydroxyl pyridine derivatives : structural, spectroscopic, magnetic and anticancer in vitro studies

Copper(ii) complexes with 2-ethylpyridine (1 and 2), 2-(hydroxyethyl)pyridine (3) and 2-(hydroxymethyl)pyridine (4) have been synthesized and characterized. All inorganic compounds have been studied by X-ray diffraction, thermogravimetry, vibrational and EPR spectroscopy as well as theoretical methods. The geometry of the complexes 1, 3 and 4 adopts nearly perfect geometry close to square planar (1, 4) or square pyramid (3) stereochemistry, respectively. The distortion of five coordinated copper(ii) ions in complex 2 indicates intermediate geometry between square pyramidal and trigonal pyramidal geometry. Further, the magnetic measurements have shown antiferromagnetic behaviour of the prepared complexes in a wide range of temperatures. The antiferromagnetic behaviour of 2 should originate from the superexchange interactions between each copper(ii) ion by the mixed chloride and μ(4)-O ion pathways. Besides, the weak antiferromagnetic character of 2 can be also attributed to the presence of intrachain exchange between dimeric units through double oxide ion. In complex 3, strong antiferromagnetic coupling between Cu(ii) centres in the Cu(2)O(2)Cl(2) moiety is found. The cytotoxicity of all compounds was tested in vitro against various cancer cell lines: human lung adenocarcinoma (A549), human breast adenocarcinoma (MCF7), human prostate carcinoma; derived from metastatic site: brain (DU-145) and two normal cell lines: human embryonic kidney (HEK293T) and human keratinocyte (HaCat). Furthermore, Pluronic P-123 micelles loaded with selected complexes (1 and 3) were proposed to overcome low solubility and to minimize systemic side effects. More detailed study revealed that complex 3 loaded inside micelles causes DU-145 cells' death with simultaneous decrease of mitochondrial membrane potential and a high level of reactive oxygen species generation. The stability of the compounds 1–4 in DMSO was confirmed by UV-Vis and FT-IR spectra studies

Liposomal binuclear Ir(III)–Cu(II) coordination compounds with phosphino-fluoroquinolone conjugates for human prostate carcinoma treatment

[Image: see text] Novel heteronuclear Ir(III)–Cu(II) coordination compounds ([Ir(η(5)-Cp*)Cl(2)Pcfx-Cu(phen)](NO(3))·1.75(CH(3)OH)·0.75(H(2)O) (1), [Ir(η(5)-Cp*)Cl(2)Pnfx-Cu(phen)](NO(3))·1.75(CH(3)OH)·0.75(H(2)O) (2), [Ir(η(5)-Cp*)Cl(2)Plfx-Cu(phen)](NO(3))·1.3(H(2)O)·1.95(CH(3)OH) (3), [Ir(η(5)-Cp*)Cl(2)Psfx-Cu(phen)] (4)) bearing phosphines derived from fluoroquinolones, namely, sparfloxacin (Hsfx), ciprofloxacin (Hcfx), lomefloxacin (Hlfx), and norfloxacin (Hnfx), have been synthesized and studied as possible anticancer chemotherapeutics. All compounds have been characterized by electrospray ionization mass spectrometry (ESI-MS), a number of spectroscopic methods (i.e., IR, fluorescence, and electron paramagnetic resonance (EPR)), cyclic voltammetry, variable-temperature magnetic susceptibility measurements, and X-ray diffractometry. The coordination geometry of Ir(III) in all complexes adopts a characteristic piano-stool geometry with the η(5)-coordinated and three additional sites occupied by two chloride and phosphine ligands, while Cu(II) ions in complexes 1 and 2 form a distorted square-pyramidal coordination geometry, and in complex 3, the coordination geometry around Cu(II) ions is a distorted octahedron. Interestingly, the crystal structure of [Ir(η(5)-Cp*)Cl(2)Plfx-Cu(phen)] features the one-dimensional (1D) metal–organic polymer. Liposomes loaded with redox-active and fluorescent [Ir(η(5)-Cp*)Cl(2)Pcfx-Cu(phen)] (1L) have been prepared to increase water solubility and minimize serious systemic side effects. It has been proven, by confocal microscopy and an inductively coupled plasma mass spectrometry (ICP-MS) analysis, that the liposomal form of compound 1 can be effectively accumulated inside human lung adenocarcinoma and human prostate carcinoma cells with selective localization in nuclei. A cytometric analysis showed dominance of apoptosis over the other cell death types. Furthermore, the investigated nanoformulations induced changes in the cell cycle, leading to S phase arrest in a dose-dependent manner. Importantly, in vitro anticancer action on three-dimensional (3D) multicellular tumor spheroids has been demonstrated

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

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

Copper(I) complexes with phosphine derived from sparfloxacin. Part I - structures, spectroscopic properties and cytotoxicity

In this paper we present new copper(I) iodide or copper(I) thiocyanate complexes with hydroxymethyldiphenylphosphine (PPh2(CH2OH)) or phosphine derivatives of sparfloxacin, a 3rd generation fluoroquinolone antibiotic agent (PPh2(CH2–Sf)) and 2,9-dimethyl-1,10-phenanthroline (dmp) or 2,2′-biquinoline (bq) auxiliary ligands. The synthesised complexes were fully characterised by NMR and UV-Vis spectroscopy as well as by mass spectrometry. Selected structures were additionally analysed using X-ray and DFT methods. All complexes proved to be stable in solution in the presence of water and atmospheric oxygen for several days. The cytotoxic activity of the complexes was tested against two cancer cell lines (CT26 – mouse colon carcinoma and A549 – human lung adenocarcinoma). Applying two different incubation times, the studies enabled a preliminary estimation of the dependence of the selectivity and the mechanism of action on the type of diimine and phosphine ligands. The results obtained showed that complexes with PPh2(CH2–Sf) are significantly more active than those with PPh2(CH2OH). On the other hand, the relative impact of diimine on cytotoxicity is less pronounced. However, the dmp complexes are characterised by strong inhibitory properties, while the bq ones are rather not. This confirms the interesting and promising biological properties of the investigated group of copper(I) complexes, which undoubtedly are worthy of further biological studies