Urszula K. Komarnicka

Solid state luminescence of copper(I) (pseudo)halide complexes with neocuproine and aminomethylphosphanes derived from morpholine and thiomorpholine

The copper(I) iodide or copper(I) isothiocyanate complexes with 2,9-dimethyl-1,10-phenanthroline (dmp) and two interesting aminomethylphosphanes: P(CH2N(CH2CH2)2O)3 (1) and novel P(CH2N(CH2CH2)2S)3 (2): CuI(dmp)P(CH2N(CH2CH2)2O)3 (1I), which was presented in our previous papers, CuI(dmp)P(CH2N(CH2CH2)2S)3 (2I), CuNCS(dmp)P(CH2N(CH2CH2)2O)3 (1T) and CuNCS(dmp)P(CH2N(CH2CH2)2S)3 (2T) are discussed in this work. The chemical structures of three new complexes were determined in solution by means of NMR spectroscopy and in solid state using X-ray measurements. For all presented complexes the coordination geometry about the Cu(I) centre is pseudo-tetrahedral showing the small flattening and large rocking distortions. All compounds crystallize as the discrete dimers bound by π-stacking interactions between dmp rings, which strongly depend on the phosphane ligand. Investigated complexes exhibit orange photoluminescence in the solid state of highly diversified intensity, position of the luminescence band and the lifetimes. On the basis of TDDFT calculations, the CT bands observed in UV-Vis spectra are assigned to the two mixed transitions from the CuX (X = I or NCS) bond with a small admixture of the CuP bond to π* orbitals of the dmp ligand: (MX,MPR3)LCT. However, emission bands can be interpreted to be of (MX)LCT type.

Phosphine derivatives of ciprofloxacin and norfloxacin, a new class of potential therapeutic agents

In this paper a new series of chalcogenides of diphenylmethylaminophosphine derived from ciprofloxacin (PPh2CH2Cp) and a new phosphine derived from norfloxacin (PPh2CH2Nr) are presented. The synthesized compounds were characterized by NMR, MS and X-ray techniques. Both phosphines exhibit antibacterial activity against: S. aureus, E. coli, K. pneumoniae and P. aeruginosa, similar to ciprofloxacin and norfloxacin. They inhibit the growth of microorganisms in relatively low concentrations. Chalcogenides are slightly less active than phosphines and unmodified antibiotics. All the derivatives were also tested in vitro as anticancer agents towards mouse colon carcinoma (CT26) and human lung adenocarcinoma (A549). Cytotoxicity studies revealed that phosphines and their chalcogenides are able to inhibit the proliferation of the cells at relatively low concentrations. Moreover, all the tested compounds are more active against tested cell lines than cisplatin – the main representative of antitumor drugs.

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.

Ruthenium(II) piano stool coordination compounds with aminomethylphosphanes: Synthesis, characterisation and preliminary biological study in vitro

Reaction of {[Ru(η6-p-cymene)Cl]2(μ-Cl)2} (1) with aminomethylphosphane derived from morpholine (P{CH2N(CH2CH2)2O}3 (A), PPh2{CH2N(CH2CH2)2O} (B)) or piperazine (P{CH2N(CH2CH2)2NCH2CH3}3 (C), PPh2{CH2N(CH2CH2)2NCH2CH3} (D)) results in four new piano stool ruthenium(II) coordination compounds: [Ru(η6-p-cymene)Cl2(A)] (2A), [Ru(η6-p-cymene)Cl2(B)] (2B), [Ru(η6-p-cymene)Cl2(C)] (2C) and [Ru(η6-p-cymene)Cl2(D)] (2D). Every complex was fully characterized using spectroscopic methods (1H, 13C{1H}, 31P{1H} NMR and ESI-MS), elemental analysis, X-ray single crystal diffraction and DFT calculations. Preliminary studies of in vitro cytotoxicity on the A549 (human lung adenocarcinoma) and MCF7 (human breast adenocarcinoma) cell lines revealed 2A-2D activity in the same order of magnitude as in the case of cisplatin. Additionally, the study confirmed the ability of 2A-2D to interact with DNA helix and transferrin.

Unexpected formation of [Ru(η5-C5H5)(PH{CH2N(CH2CH2)2O}2)(PPh3)2]BF4 – the first “piano-stool” ruthenium complex bearing a secondary aminomethylphosphane ligand

In this paper we report the reaction of [Ru(η5-C5H5)Cl(PPh3)2] with P{CH2N(CH2CH2)2O}3 in the presence of NaBF4, in which, apart from the Cl− substitution, an unexpected P–C bond cleavage in the tertiary phosphane is observed. It results in the formation of [Ru(η5-C5H5)(PH{CH2N(CH2CH2)2O}2)(PPh3)2]BF4 (1) – the first “piano-stool” ruthenium complex with a secondary aminomethylphosphane ligand.

Cu I and Cu II complexes with phosphine derivatives of fluoroquinolone antibiotics – A comparative study on the cytotoxic mode of action

In this paper, we present a comparative study on the cytotoxic mode of action of copper(I) and copper(II) complexes with phosphine derivatives of fluoroquinolone antibiotics (ciprofloxacin HCp and norfloxacin HNr). The in vitro cytotoxic activity of four new compounds was tested against two selected cancer cell lines. All complexes exhibited much better cytotoxicity against both cell lines than unmodified fluoroquinolone antibiotics, their phosphines (PCp, PNr), chalcogenide derivatives (oxides: OPCp, OPNr; sulfides: SPCp, SPNr and selenides: SePCp, SePNr) and previously described by us complexes with phosphines derived from different fluoroquinolones: lomefloxacin (HLm) and sparfloxacin (HSf) as well as cisplatin. Apoptosis, observed at a great predominance, was induced by all studied complexes. Importantly, it was concluded that coordination compounds with Cu(I) ion ([CuI-PNr] and [CuI-PCp]) were much more active than those with Cu(II) ion ([OPNr-CuII], [OPCp-CuII]), even though the highest efficacy to produce reactive oxygen species, participating in overall cytotoxicity, was proved for copper(II) complexes among all studied compounds. Herein, we discuss not only results obtained for copper(I)/(II) complexes with phosphines derived from HNr and HCp but we also compare them to previously described data for complexes with HLm and HSf derivatives. This is the first insight into a structure-activity relationship of copper complexes with phosphine derivatives of fluoroquinolone antibiotics.

Selective Cu(I) complex with phosphine-peptide (SarGly) conjugate contra breast cancer: Synthesis, spectroscopic characterization and insight into cytotoxic action

The main disadvantage of conventional anticancer chemotherapy is the inability to deliver the correct amount of drug directly to cancer. Those molecular delivering systems are very important to destroy cancer cells selectively. Herein we report synthesis of phosphine-peptide conjugate (Ph2PCH2-Sar-Gly-OH, PSG) derived from SarGly (sarcosine-glycine), which can be easily exchanged to other peptide carriers, its oxide (OPh2PCH2-Sar-Gly-OH, OPSG) and the first copper(I) complex ([CuI(dmp)(P(Ph)2CH2-Sar-Gly-OH)], 1-PSG, where dmp stands for 2,9-dimethyl-1,10-phenanthroline). The compounds were characterized by elemental analysis, NMR (1D, 2D), UV-Vis spectroscopy and DFT (Density Functional Theory) methods. PSG and 1-PSG proved to be stable in biological medium in the presence of atmospheric oxygen for several days. The cytotoxicity of the compounds and cisplatin was tested against cancer cell lines: mouse colon carcinoma (CT26; 1-PSGIC50 = 3.12 ± 0.1), human lung adenocarcinoma (A549; 1-PSGIC50 = 2.01 ± 0.2) and human breast adenocarcinoma (MCF7; 1-PSGIC50 = 0.98 ± 0.2) as well as against primary line of human pulmonary fibroblasts (MRC-5; 1-PSGIC50 = 78.56 ± 1.1). Therapeutic index for 1-PSG (MCF7) equals 80. Intracellular accumulation of 1-PSG complex increased with time and was much higher (96%) inside MCF7 cancer cells than in normal MRC5 cells (20%). Attachment of SarGly to cytotoxic copper(I) complex via phosphine motif improved selectivity of copper(I) complex 1-PSG into the cancer cells. Precise mechanistic study revealed that the 1-PSG complex causes apoptotic cells MCF7 death with simultaneous decrease of mitochondrial membrane potential and increase of caspase-9 and -3 activities. Additionally, 1-PSG generated high level of reactive oxygen species that was the reason for oxidative damages to the sugar-phosphate backbone of plasmid DNA.

Polymeric micelle-mediated delivery of half-sandwich ruthenium(II) complexes with phosphanes derived from fluoroloquinolones for lung adenocarcinoma treatment

Graphical abstract Figure. No caption available. HighlightsHalf‐sandwich Ru(II) complexes with phosphanes derived from fluoroloquinolones are synthesized.Half‐sandwich Ru(II) complexes intercalate with DNA not causing conformation changes.Half‐sandwich Ru(II) complexes cause cleavage of a single DNA strand.Polymeric micelles loaded with Ru(II) complexes enable efficient complex accumulation inside cancer cells.Polymeric micelles loaded with Ru(II) complexes exhibit promising anticancer activity in vitro. Abstract Novel half‐sandwich ruthenium(II) complexes with aminomethyl(diphenyl)phosphine derived from fluoroloquinolones (RuPCp, RuPSf, RuPLm, RuPNr) were being investigated as alternatives to well‐established metal‐based chemotherapeutics. All compounds were characterized by elemental analysis, selected spectroscopic methods (i.e., absorption and fluorescence spectroscopies, ESI‐MS, NMR, circular dichroizm), X‐ray diffractometry, ICP‐MS, and electrochemical techniques. To overcome low solubility, serious side effects connected with systemic cytotoxicity of ruthenium complexes, and acquiring the resistance of cancer cells, polymeric nanoformulations based on Pluronic P‐123 micelles loaded with selected Ru(II) complexes were prepared and characterized. Resulting micelles (RuPCp_M, RuPNr_M) enabled efficient drug accumulation inside human lung adenocarcinoma (A549 tumor cell line), proved by confocal microscopy and ICP‐MS analysis, allowing cytotoxic action. Studied complexes exhibited promising cytotoxicity in vitro with IC50 values significantly lower than the reference drug – cisplatin. The fluorescence spectroscopic data (CT‐DNA titration, in vitro cell staining) together with analysis of DNA fragmentation (pBR322 plasmid, comet assay) provided clear evidence for the interaction with DNA inducing apoptotic cell death.

Impact of the Cu(II) ions on the chemical and biological properties of goserelin – coordination pattern, DNA degradation, oxidative reactivity and in vitro cytotoxicity

Goserelin acetate (Gos) as a synthetic analog of the mammalian gonadotropin-releasing hormone (GnRH) is widely used in the treatment of sex hormone-related conditions. In this paper we present the chemical and biological aspects of its interaction with Cu(II) ions. The mode of Cu(II) binding and the thermodynamic stability of the obtained complexes were characterized by potentiometry, UV-Vis and CD spectroscopic methods. The DFT calculations were applied in order to investigate and confirm the molecular structure of the studied systems. The experimental and theoretical results clearly indicated the involvement of three nitrogens from the peptide and two oxygens from the acetate moieties in the Cu(II) coordination under physiological conditions. The investigated metallopeptide caused single- and/or double cleavage of the sugar-phosphate backbone of the plasmid DNA in the reaction accompanied by endogenous substances such as hydrogen peroxide or ascorbic acid. The degradation of the DNA molecule occurred via the free radical mechanism. Calculations based on measured spectra allowed determining the kinetic parameters of OH formation. The cytotoxic effects of Gos and its metallo-derivative were tested in vitro towards two cancer cell lines (A549 - human lung adenocarcinoma, CT26 - mouse colon carcinoma).

Di-μ-iodido-bis-[(dimethyl 2,2'-biquinoline-4,4'-dicarboxyl-ate-κ(2)N,N')copper(I)].

In the centrosymmetric dinuclear title complex, [Cu2I2(C22H16N2O4)2], the CuI atom is coordinated in a distorted tetrahedral geometry by an N,N′-bidentate dimethyl 2,2′-biquinoline-4,4′-dicarboxylate ligand and two symmetry-related I atoms, which act as bridges to a symmetry-related CuI atom. The distance between the CuI atoms within the dinuclear unit is 2.6723 (11) Å.