Antibactericidal Ir(III) and Ru(II) Complexes with Phosphine-Alkaloid Conjugate and Their Interactions with Biomolecules: A Case of N-Methylphenethylamine.

The phosphine ligand (Ph2 PCH2 N(CH3 )(CH2 )2 Ph, PNMPEA) obtained by the reaction of the (hydroxymethyl)diphenylphosphine with naturally occurring alkaloid N-methylphenethylamine, was used to synthesize the half-sandwich iridium(III) (Ir(η5 -Cp*)Cl2 Ph2 PCH2 N(CH3 )(CH2 )2 Ph, IrPNMPEA) and ruthenium(II) (Ru(η6 -p-cymene)Cl2 Ph2 PCH2 N(CH3 )(CH2 )2 Ph, RuPNMPEA) complexes. They were characterized using a vast array of methods, including 1D and 2D NMR, ESI(+)MS spectrometry, elemental analysis, cyclic voltammetry (CV), electron spectroscopy in the UV-Vis range (absorption, fluorescence) and density functional theory (DFT). The initial antimicrobial activity in vitro toward Gram-positive and Gram-negative bacterial strains was examined, indicating that both complexes are selective towards Gram-positive bacteria, e. g., Staphylococcus aureus, where the IrPNMPEA has been more bactericidal compared to RuPNMPEA. Additionally, the interactions of these compounds with various biomolecules, such as DNA (ctDNA, plasmid DNA, 9-ethylguanine (9-EtG), and 9-methyladenine (9-MeA)), nicotinamide adenine dinucleotide (NADH), glutathione (GSH), and ascorbic acid (Asc) were described. The results showed that both Ir(III) and Ru(II) complexes accelerate the oxidation process of NADH, GSH and Asc that appeared to occur by an electron transfer mechanism. Interestingly, only IrPNMPEA leads to the formation of various biomolecule adducts, which can explain its higher activity. Furthermore, RuPNMPEA and IrPNMPEA have been interacting with the DNA through weak noncovalent interactions.

Liposomal Binuclear Ir(III)-Cu(II) Coordination Compounds with Phosphino-Fluoroquinolone Conjugates for Human Prostate Carcinoma Treatment.

Novel heteronuclear IrIII-CuII coordination compounds ([Ir(η5-Cp*)Cl2Pcfx-Cu(phen)](NO3)·1.75(CH3OH)·0.75(H2O) (1), [Ir(η5-Cp*)Cl2Pnfx-Cu(phen)](NO3)·1.75(CH3OH)·0.75(H2O) (2), [Ir(η5-Cp*)Cl2Plfx-Cu(phen)](NO3)·1.3(H2O)·1.95(CH3OH) (3), [Ir(η5-Cp*)Cl2Psfx-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 IrIII in all complexes adopts a characteristic piano-stool geometry with the η5-coordinated and three additional sites occupied by two chloride and phosphine ligands, while CuII ions in complexes 1 and 2 form a distorted square-pyramidal coordination geometry, and in complex 3, the coordination geometry around CuII ions is a distorted octahedron. Interestingly, the crystal structure of [Ir(η5-Cp*)Cl2Plfx-Cu(phen)] features the one-dimensional (1D) metal-organic polymer. Liposomes loaded with redox-active and fluorescent [Ir(η5-Cp*)Cl2Pcfx-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.

Synthesis, physicochemical characterization and antiproliferative activity of phosphino Ru(II) and Ir(III) complexes.

Herein, we present the synthesis of new complexes based on ruthenium(II) (Ru(η6-p-cymene)Cl2PPh2CH2OH (RuPOH) and Ru(η6-p-cymene)Cl2P(p-OCH3Ph)2CH2OH (RuMPOH)) and iridium(III) (Ir(η5-Cp*)Cl2P(p-OCH3Ph)2CH2OH (IrMPOH) and Ir(η5-Cp*)Cl2PPh2CH2OH (IrPOH)) containing phosphine ligands with/without methoxy motifs on phenyl rings (P(p-OCH3Ph)2CH2OH (MPOH) and PPh2CH2OH (POH)). The complexes were characterized by mass spectrometry, NMR spectroscopy (1D: 1H, 13C{1H}, and 31P{1H} and 2D: HMQC, HMBC, and COSY NMR) and elemental analysis. All the complexes were structurally identified by single-crystal X-ray diffraction analysis. The Ru(II) and Ir(III) complexes have a typical piano-stool geometry with an η6-coordinated arene (RuII complexes) or η5-coordinated (IrIII compounds) and three additional sites of ligation occupied by two chloride ligands and the phosphine ligand. Oxidation of NADH to NAD+ with high efficiency was catalyzed by complexes containing P(p-OCH3Ph)2CH2OH (IrMPOH and RuMPOH). The catalytic property might have important future applications in biological and medical fields like production of reactive oxygen species (ROS). Furthermore, the redox activity of the complexes was confirmed by cyclic voltamperometry. Biochemical assays demonstrated the ability of Ir(III) and Ru(II) complexes to induce significant cytotoxicity in various cancer cell lines. Furthermore, we found that RuPOH and RuMPOH selectively inhibit the proliferation of skin cancer cells (WM266-4; IC50, after 24 h: av. 48.3 µM; after 72 h: av. 10.2 µM) while Ir(III) complexes were found to be moderate against prostate cancer cells (DU145).

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 µ4-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 Cu2O2Cl2 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.

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.

Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug.

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.

Isothiocyanate l-argininato copper(II) complexes - Solution structure, DNA interaction, anticancer and antimicrobial activity.

l-argininato copper(II) complexes have been intensively investigated in a variety of diseases due to their therapeutic potential. Here we report the results of comprehensive structural studies (ESI-MS, NIR-VIS-UV, EPR) on the complexes arising in aqueous solutions of two ternary copper(II) complexes with molecular formulas from crystal structures, [Cu(l-Arg)2(NCS)](NCS)·H2O (1) and [Cu(l-Arg)(NCS)2] (2) (l-Arg = l-arginine). Reference systems, the ternary Cu(II)/l-Arg/NCS- as well as binary Cu(II)/NCS- and Cu(II)/l-Arg, were studied in parallel in aqueous solutions by pH-potentiometric titration, EPR and VIS spectroscopy to characterize stability, structures and speciation of the formed species over the broad pH range. Comparative analysis of the obtained results showed that at a pH close to 7.0 mononuclear [Cu(l-Arg)2(NCS)]+ is the only species in water solution of 1, while equilibrium between [Cu(l-Arg)(SCN)]+ and binary [Cu(l-Arg)2]2+ was detected in water solution of 2. According to DNA binding studies, the [Cu(l-Arg)2(NCS)]+, [Cu(l-Arg)(SCN)]+ and [Cu(l-Arg)2]2+ species could be considered as strong minor groove binding agents causing, in the presence of H2O2, the involvement of ROS in plasmid damage. The human carcinoma cells (A549 cell line) were generally significantly more sensitive to cytotoxic and antiproliferative effect of compounds 1 and 2 than human normal cells. The studied compounds shown antimicrobial activity against bacteria belonging to Enterobacteriaceae family.

Antibacterial activity and action mode of Cu(I) and Cu(II) complexes with phosphines derived from fluoroquinolone against clinical and multidrug-resistant bacterial strains.

Biological activity against reference and multi-drug resistant (MDR) clinical strains of fluoroquinolones (FQs): ciprofloxacin (HCp), norfloxacin (HNr), lomefloxacin (HLm) and sparfloxacin (HSf), phosphine ligands derived from those antibiotics and 14 phosphino copper(I) and copper(II) complexes with 2,9-dimethyl-1,10-phenanthroline, 1,10-phenanthroline or 2,2'-biquinoline have been determined. Almost all phosphines showed excellent antibacterial activity relative to reference strains (S. aureus ATCC 6538, E. coli ATCC 25922, K. pneumoniae ATCC 4352, and P. aeruginosa ATCC 27853). In rare cases P. aeruginosa rods showed natural insensitivity to oxides, and their copper(II) complexes. Most of the studied compounds showed weak antibacterial activity against clinical multi-drug resistant strains (MDR P. aeruginosa 16, 46, 325, 355, MRD A. baumanii 483 and MDR S. aureus 177). However, phosphines Ph2PCH2Sf (PSf), Ph2PCH2Lm (PLm) and their copper(I) complexes were characterized by the best antibacterial activity. In addition, PSf compounds, in which the activities relative to P. aeruginosa MDRs were relatively diverse, paid particular attention in our studies. Genetic and phenotypic studies of these strains showed significant differences between the strains, indicating different profiles of FQs resistance mechanisms. This may prove that a change in the spatial conformation of the PSf derivatives relative to the native form of HSf increased its affinity for the target site of action in gyrase, leading to selective inhibition of the multiplication of MDR strains. In conclusion, differences in PSf activity within closely related P. aeruginosa strains may indicate its diagnostic and therapeutic potential.

Copper(I) complexes with phosphines P(p-OCH3-Ph)2CH2OH and P(p-OCH3-Ph)2CH2SarGly. Synthesis, multimodal DNA interactions, and prooxidative and in vitro antiproliferative activity.

Phosphonium salt (p-OCH3-Ph)2P(CH2OH)2Cl (MPOHC), derived phosphine ligands without and with SarGly (Sarcosine-Glycine) peptide carrier P(p-OCH3-Ph)2CH2OH (MPOH) and P(p-OCH3-Ph)2CH2SarGly (MPSG), respectively, and two copper(I) complexes [Cu(I)(dmp)(MPOH)] (1-MPOH; dmp = (2,9-dimethyl-1,10-phenanthroline)) and [Cu(I)(dmp)(MPSG)] (1-MPSG) were synthesized. The resulting compounds were characterized by elemental analysis, 1D and 2D NMR and UV-Vis absorption spectroscopies, mass spectrometry, cyclic voltammetry and by X-ray diffraction analysis. Cytotoxicity of all compounds was evaluated in vitro against colon, lung, breast, pancreatic, prostate tumor cell lines, as well as towards non-tumor cell lines: lung, kidney and keratinocyte. Stable in biological medium in the presence of atmospheric oxygen, Cu(I) complexes exerted a cytotoxic effect higher than that elicited by cisplatin against tested cancer cell lines. The introduction of methoxy group onto the phenyl rings of the phosphine ligand coordinated to the copper(I) ion resulted in a relevant increase of cytotoxicity in the case of breast, pancreatic and prostate tumor cell lines in vitro. Attachment of a peptide carrier significantly increased the selectivity towards cancer cells. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA) titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of copper compounds with DNA and showed their unusual low genotoxicity. Additionally, copper complexes were able to generate reactive oxygen species as a result of redox processes, proved by fluorescence spectroscopy and cyclic voltamperometry.

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 ±â€¯0.1), human lung adenocarcinoma (A549; 1-PSGIC50 = 2.01 ±â€¯0.2) and human breast adenocarcinoma (MCF7; 1-PSGIC50 = 0.98 ±â€¯0.2) as well as against primary line of human pulmonary fibroblasts (MRC-5; 1-PSGIC50 = 78.56 ±â€¯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.