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Four mono- (1–4) and four binuclear Ru(II) arene (5–8) complexes have been isolated from the reaction of [Ru(η6-benzene)Cl(μ-Cl)]2 or [Ru(η6-toluene)Cl(μ-Cl)]2 with 2-pyridinecarboxylic acid and 6-fluoro-2-pyridinecarboxylic acid. Their structural characterization included IR and NMR spectroscopy and MS spectrometry. The cytotoxic potential of the compounds has been tested by MTT assay in seven human cancer cell lines: alveolar basal adenocarcinoma (A549), large cell lung carcinoma (HTB177), colorectal carcinoma (HCT116), malignant melanoma (A375), prostate adenocarcinoma (PC3), breast carcinoma (MDA-MB-453), cervix adenocarcinoma (HeLa), and one human non-malignant lung fibroblast cell line (MRC-5). Mononuclear complexes 1 and 3 carrying 2-pyridinecarboxylic acid have displayed moderate antiproliferative effect toward HCT116 and HeLa, slightly better in comparison to their binuclear analogues, 5 and 7. The highest activity and cytoselectivity has been observed 1 as it has reduced viability of HCT116 cells 1.5 times more efficiently (IC50 = 27.5 μM), than of the MRC-5 cells (IC50 = 41.3 μM). In contrast to 1 and 3, compounds 2, 4–8 have been found to exhibit lack of cytotoxicity or mild cytotoxicity with IC50 values ranging from 100 to 300 μM. This is peer-reviewed version of the following article: Nikolić, S.; Mihajlović-Lalić, L. E.; Vidosavljević, M.; Aranđelović, S.; Radulović, S.; Grgurić-Šipka, S. Mono- and Binuclear Ru(II) Arene Complexes with (Fluoro Substituted) Picolinic Acid: Synthesis, Characterization and Cytotoxicity. Journal of Organometallic Chemistry 2019, 902. [https://doi.org/10.1016/j.jorganchem.2019.120966] Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3642]

Coordinate and redox interactions of epinephrine (Epi) with iron at physiological pH are essential for understanding two very different phenomena - the detrimental effects of chronic stress on the cardiovascular system and the cross-linking of catecholamine-rich biopolymers and frameworks. Here we show that Epi and Fe3+ form stable high-spin complexes in the 1:1 or 3:1 stoichiometry, depending on the Epi/Fe3+ concentration ratio (low or high). Oxygen atoms on the catechol ring represent the sites of coordinate bond formation within physiologically relevant bidentate 1:1 complex. Redox properties of Epi are slightly impacted by Fe3+. On the other hand, Epi and Fe2+ form a complex that acts as a strong reducing agent, which leads to the production of hydrogen peroxide via O-2 reduction, and to a facilitated formation of the Epi-Fe3+ complexes. Epi is not oxidized in this process, i.e. Fe2+ is not an electron shuttle, but the electron donor. Epi-catalyzed oxidation of Fe2+ represents a plausible chemical basis of stress-related damage to heart cells. In addition, our results support the previous findings on the interactions of catecholamine moieties in polymers with iron and provide a novel strategy for improving the efficiency of cross-linking. Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3040]

Pt/Ru-doped ZnO nanophase particles were synthesized using ultrasonic spray pyrolysis. Particles were obtained through decomposition of zinc nitrate and newly developed Pt(IV) and Ru(III) complexes. The particle morphology, phase composition and chemical structure were revealed in accordance to various analysis methods (XRD, DSC, SEWEDS, TEM) and discussed in terms of precursor chemistry and process parameters. The shape of DSC curves, indicating two exothermic effects above 600 degrees C in both ZnO:Ru and ZnO:Pt, gave an indication of irreversible structural changes and high reactivity of as-prepared powders. The hexagonal wurtzite-type ZnO phase was revealed in both powdered samples. Small content of an intermediate Zn-5(NO3)(2)(OH)(8)(.)2H(2)O and cubic Zn2PtO4 phase were detected in the Pt-doped ZnO particles. Structural refinements, performed by Koalariet-XFit, suggest the composite internal particle structure composed of primary particles sized less than 100 nm. The estimated values for the unit cell parameters and Zn-O bond lengths imply noble metal ions incorporation into ZnO matrix interstitially, probably in octahedral interstitial environment. It has been shown that different particle growing morphologies (either spheroidally or pyramidally shaped) were influenced by the precursor chemistry, processing parameters and the presence of noble metal ions. Among the many parameters, attaining of the particle shape uniformity and homogeneous distribution of the noble metal cations in as-prepared particles are regarded as the most important factors for dominating microstructure evolution.

Some uns-cis-(ethylendiamine-N,N'-di-3-propionato)cobalt(III) complexes with symmetrical beta-diketonato ligands, 2,4-pentanedione, 1,3-diphenyl-1,3-propanedione and 2,2,6,6-tetramethyl-3,5-heptanedione, have been prepared by the reaction of sodium uns-cis-(ethylenediamine-N,N'-di-3-propionato)(carbonato)cobaltate(III) and the corresponding diketone at 75 degrees C. The complexes were isolated chromatographically and characterized by elemental analysis, infrared and electron absorption spectroscopy.

Some uns-cis-(ethylendiamine-N,N'-di-3-propionato)cobalt(III) complexes with symmetrical β-diketonato ligands, 2,4-pentanedione, 1,3-diphenyl-1,3-propanedione and 2,2,6,6-tetramethyl-3,5-heptanedione, have been prepared by the reaction of sodium uns-cis-(ethylenediamine-N,N'-di-3-propionato)(carbonato)cobaltate(III) and the corresponding diketone at 75°C. The complexes were isolated chromatographically and characterized by elemental analysis, infrared and electron absorption spectroscopy.

In search for antitumor metal-based drugs that would mitigate the severe side-effects of cisplatin, Ru(II) complexes are gaining increasing recent interest. In this work, we report on the synthesis, characterization (1H- and 13C-NMR, FT-IR), and cytotoxicity studies of two new half-sandwich organometallic Ru(II) complexes of the general formula [Ru(η6-arene)(XY)Cl](PF6) where arene = benzene or toluene and XY = bidentates: dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip), which are bound to Ru(II) via two phenanthroline-N atoms in a characteristic “piano-stool” configuration of Ru(II)-arene complexes—as confirmed by vibrational and NMR spectra. In addition, cytotoxic studies were performed for similar half-sandwich organometallic [Ru(η6-p-cymene)(Me2dppz)Cl]PF6 complex (Me2dppz = 11,12-dimethyl-dipyrido[3,2-a:2′,3′-c]phenazine). This study is complemented with elaborate modeling with density functional theory (DFT) calculations, which provided insight into reactive sites of Ru(II) structures, further detailed by molecular docking on the B-DNA dodecamer, which identified binding sites and affinities: most pronounced for the [Ru(η6-benzene)(aip)Cl](PF6) in both A-T and G-C regions of the DNA minor groove. Cytotoxic activity was probed versus tumor cell lines B16, C6, and U251 (B16 mouse melanoma, C6 rat glioma, U251 human glioblastoma) and non-tumor cell line HACAT (HACAT normal human keratinocytes).

Complexes 1–4, [Ru(L)(bpy)2]PF6, where bpy = 2,2′-bipyridine; HL = 3-methylpyridine-2-carboxylic acid (HL1), 6-methylpyridine-2-carboxylic acid (HL2), 5-bromopyridine-2-carboxylic acid (HL3) and 6-bromopyridine-2-carboxylic acid (HL4), were synthesized and characterized. The electrochemical character of the complexes was investigated by cyclic voltammetry revealing two reversible reduction waves in the negative range of potentials, most likely due to a reduction of the bipyridine moiety. Cytotoxicity studies by MTT assay for 72 h of drug action revealed that 2–4 exhibited moderate activity in cervical human tumor cells (HeLa). Complex 2 exhibited low activity in colon cancer LS-174 cells (180 ± 10), while all complexes were devoid of activity in lung cancer A549 and non-tumor MRC-5 cells, up to 200 μM. Combinational studies of the most active complex 2, with pharmacological modulators of cell redox status, L-buthionine-sulfoximine (L-BSO) or N-acetyl-L-cysteine (NAC), showed that when L-BSO potentiated, 2 induced a sub-G1 peak of the cell cycle in the HeLa cell line. UV–vis and cyclic voltammetry were performed in order to investigate the binding mode of 2 to DNA and suggested intercalation for the complex–DNA interaction.

In search for antitumor metal-based drugs that would mitigate the severe side-effects of cisplatin, Ru(II) complexes are gaining increasing recent interest. In this work, we report on the synthesis, characterization (1H- and 13C-NMR, FT-IR), and cytotoxicity studies of two new half-sandwich organometallic Ru(II) complexes of the general formula [Ru(η6-arene)(XY)Cl](PF6) where arene = benzene or toluene and XY = bidentates: dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip), which are bound to Ru(II) via two phenanthroline-N atoms in a characteristic “piano-stool” configuration of Ru(II)-arene complexes—as confirmed by vibrational and NMR spectra. In addition, cytotoxic studies were performed for similar half-sandwich organometallic [Ru(η6-p-cymene)(Me2dppz)Cl]PF6 complex (Me2dppz = 11,12-dimethyl-dipyrido[3,2-a:2′,3′-c]phenazine). This study is complemented with elaborate modeling with density functional theory (DFT) calculations, which provided insight into reactive sites of Ru(II) structures, further detailed by molecular docking on the B-DNA dodecamer, which identified binding sites and affinities: most pronounced for the [Ru(η6-benzene)(aip)Cl](PF6) in both A-T and G-C regions of the DNA minor groove. Cytotoxic activity was probed versus tumor cell lines B16, C6, and U251 (B16 mouse melanoma, C6 rat glioma, U251 human glioblastoma) and non-tumor cell line HACAT (HACAT normal human keratinocytes).

In search for antitumor metal-based drugs that would mitigate the severe side-effects of cisplatin, Ru(II) complexes are gaining increasing recent interest. In this work, we report on the synthesis, characterization (1H- and 13C-NMR, FT-IR) and cytotoxicity studies of two new half-sandwich organometallic Ru(II) complexes of the general formula [Ru(η6-arene)(XY)Cl](PF6) where arene = benzene or toluene and XY = bidentates: dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip), which are bound to Ru(II) via two phenanthroline-N atoms in a characteristic "piano-stool" configuration of Ru(II)-arene complexes - as confirmed by vibrational and NMR spectra. In addition, cytotoxic studies were performed for similar half-sandwich organometallic [Ru(η6-p-cymene)(Me2dppz)Cl]PF6 complex (Me2dppz =11,12-dimethyl-dipyrido[3,2-a:2′,3′-c]phenazine). This study is complemented with elaborate modeling with density functional theory (DFT) calculations, which provided insight into reactive sites of Ru(II) structures, further detailed by Molecular Docking on the B-DNA dodecamer, which identified binding sites and affinities: most pronounced for the [Ru(η6-benzene)(aip)Cl](PF6) in both A-T and G-C regions of the DNA minor groove. Cytotoxic activity was probed versus tumor cell lines B16, C6 and U251 (B16 mouse melanoma, C6 rat glioma, U251 human glioblastoma) and non-tumor cell line HACAT (HACAT normal human keratinocytes).

Complexes 1-4, [Ru(L)(bpy)2]PF6, where bpy = 2,2′-bipyridine; L = 3-methylpyridine-2-carboxylic acid (L1), 6-methylpyridine-2-carboxylic acid (L2), 5-bromopyridine-2-carboxylic acid (L3) and 6-bromopyridine-2-carboxylic acid (L4), were synthesized and characterized. The electrochemical character of the complexes was investigated by cyclic voltammetry revealing two reversible reduction waves in the negative range of potentials, most likely due to a reduction of the bipyridine moiety. Cytotoxicity studies by MTT assay for 72 h of drug action revealed that 2-4 exhibited moderate activity in cervical human tumor cells (HeLa). Complex 2 exhibited low activity in colon cancer LS-174 cells (180 ± 10), while all complexes were devoid of activity in lung cancer A549 and non-tumor MRC-5 cells, up to 200 μM. Combinational studies of the most active complex 2, with pharmacological modulators of cell redox status, L-buthionine-sulfoximine (L-BSO) or N-acetyl-L-cysteine (NAC), showed that when L-BSO potentiated, 2 induced a sub-G1 peak of the cell cycle in the HeLa cell line. UV-vis and cyclic voltammetry were performed in order to investigate the binding mode of 2 to DNA and suggested intercalation for the complex-DNA interaction.

Complexes 1–4, [Ru(L)(bpy)2]PF6, where bpy = 2,2′-bipyridine; HL = 3-methylpyridine-2-carboxylic acid (HL1), 6-methylpyridine-2-carboxylic acid (HL2), 5-bromopyridine-2-carboxylic acid (HL3) and 6-bromopyridine-2-carboxylic acid (HL4), were synthesized and characterized. The electrochemical character of the complexes was investigated by cyclic voltammetry revealing two reversible reduction waves in the negative range of potentials, most likely due to a reduction of the bipyridine moiety. Cytotoxicity studies by MTT assay for 72 h of drug action revealed that 2–4 exhibited moderate activity in cervical human tumor cells (HeLa). Complex 2 exhibited low activity in colon cancer LS-174 cells (180 ± 10), while all complexes were devoid of activity in lung cancer A549 and non-tumor MRC-5 cells, up to 200 μM. Combinational studies of the most active complex 2, with pharmacological modulators of cell redox status, L-buthionine-sulfoximine (L-BSO) or N-acetyl-L-cysteine (NAC), showed that when L-BSO potentiated, 2 induced a sub-G1 peak of the cell cycle in the HeLa cell line. UV–vis and cyclic voltammetry were performed in order to investigate the binding mode of 2 to DNA and suggested intercalation for the complex–DNA interaction.

The four novel complexes [{cis-PtCl(NH3)2(μ-4,4'-bipyridyl)ZnCl(terpy)}](ClO4)2(C1), [{trans-PtCl(NH3)2(μ-4,4'-bipyridyl)ZnCl(terpy)}](ClO4)2(C2), [{cis-PtCl(NH3)2(μ-pyrazine)ZnCl(terpy)}](ClO4)2(C3) and [{trans-PtCl(NH3)2(μ-pyrazine)ZnCl(terpy)}](ClO4)2(C4) (where terpy = 2,2':6',2''-terpyridine) were synthesized and characterized. Acid-base titrations and concentration dependent kinetic measurements for the reactions with biologically relevant ligands such as guanosine-5'-monophosphate (5'-GMP), inosine-5'-monophosphate (5'-IMP) and glutathione (GSH), were studied at pH 7.4 and 37 °C. The binding of the heterometallic bridged cis- or trans-Pt(II)-Zn(II) complexes to calf thymus DNA (CT-DNA) was studied by UV absorption and fluorescence emission spectroscopy and molecular docking. The results indicated that the complexes bind strongly to DNA, through groove binding, hydrogen bonds, and hydrophobic or electrostatic interaction. The possible in vitro DNA protective effect of cis- and trans-Pt-L-Zn complexes has shown that C3 had significant dose-dependent DNA-protective effect and the same ability to inhibit peroxyl as well as hydroxyl radicals. Antiproliferative effect of the complexes, mRNA expression of apoptosis and repair-related genes after treatment in cancer cells indicated that newly synthesized C2 exhibited highly selective cytotoxicity toward colon carcinoma HCT116 cells. Only treatment with trans analog C2 induced effect similar to the typical DNA damaging agent such as cisplatin, characterized by p53 mediated cell response, cell cycle arrest and certain induction of apoptotic related genes. Both cis- and trans-isomers C1 and C2 showed potency to elicit expression of PARP1 mRNA and in vitro DNA binding.