Design and modulation of selectivity toward vanadium(V) and uranium(VI) ions: coordination properties and affinity of hydroxylamino-triazine siderophores

Based on the strong binding and high selectivity properties of 2,6-bis[hydroxy(methyl)amino]-4-morpholino-1,3,5-triazine (H2bihyat) for [UVIO2]2+, novel binucleating ligands (BLs) N,N′,N″,N‴-((1,4-phenylenebis(oxy))bis(1,3,5-triazine-6,2,4-triyl))tetrakis(N-methylhydroxylamine) (H4qtn), N1,N4-bis(4,6-bis(hydroxy(methyl)amino)-1,3,5-triazin-2-yl)benzene-1,4-diamine (H4pdl), and N1,N2-bis(4,6-bis(hydroxy(methyl)amino)-1,3,5-triazin-2-yl)ethane-1,2-diamine (H4enl) were synthesized. Binuclear complexes formed by coordination of hard metal ions with H4qtn are thermodynamically more stable than their mononuclear analogues with H2bihyat due to the increase in entropy accompanying the formation of more chelate rings. Reaction of either H4qtn or H4pdl or H4enl with [UVIO2]2+ and [VVO2]+ resulted in the isolation of the binuclear complexes [(UVIO2)2(μ-qtn)(H2O)4] (1), [(VVO2)2(μ-qtn)][PPh4]2[PPh4] (2), [(UVIO2)2(μ-pdl)(H2O)2(MeOH)2] (3), [(VVO2)2(μ-pdl)][PPh4]2 (4), [(UVIO2)2(μ-enl)(H2O)4] (5), and [(VVO2)2(μ-enl)][PPh4]2 (6). The binuclear complexes 1–6 were characterized by single-crystal X-ray diffraction analysis in solid state and by NMR and ESI-MS in solution. The comparison of the coordination ability of the BLs with either pyridine-2,6-dicarboxylic acid (H2dipic) or H2bihyat or CO32– toward [UVIO2]2+ and [VVO2]+ was investigated by NMR and UV–vis spectroscopies and DFT theoretical calculations, revealing a superior performance of BLs. The selectivity of the BLs for [UVIO2]2+ over [VVO2]+ is decreased compared to that of H2bihyat but increases considerably at pH > 9 values. Formation of the mixed-metal binuclear species [UVIO2(μ-O)VVO2] influences the selectivity and dynamics of the reaction of H4qtn for [UVIO2]2+ and [VVO2]+ in aqueous solution. The results of this study provide crucial information for the ligand design and the development of stronger and more selective systems

Σύνθεση και Χαρακτηρισμός Βιολογικά Ενεργών Οξειδοαναγωγικών μορίων Βαναδίου με Πολυφαινικούς υποκαταστάτες

In this work, we introduce new transition metal complexes with phenolic ligands which are models for the study of metabolic pathways in food matrixes and biological systems. In addition, there was a study upon the mechanism of radicals that created with the interaction of the phenols with metal ions. That possibility was in great interest because of the use of those kinds of systems as anticancer drugs. Finally, we developed an analytical method in order to be able to evaluate these phenol molecules in biological systems. In particular, hydroquinones and tocopherols were fluoro-labelled and vanadium labelled to be easily observed and evaluated with 19F and 51V NMR, EPR and UV-Vis spectroscopy. The quantification of the molecules using the 19F NMR took place in olive oil environment which is very like the cell membrane environment. The antioxidant action of the metal-organic molecules with the metal ions, in addition with the radical induced mechanisms were evaluated with spectroscopy, crystallography and electrochemically. Antioxidants are components of foods and there are biomolecules that are necessary for the ordinary function of human body. They used as conservatives in food matrixes against oxidation. Hydroquinones are model molecules for antioxidants and tocopherols containing a saturated phytyl chain and a different placement of methyl groups on the chromanol ring. Tocotrienol isoforms have an unsaturated side chain. Vitamin E is a generic term that represents a family of compounds composed of various tocopherol and tocotrienol isoforms. Tocopherols display potent anti-angiogenic and antiproliferative activities. Redox silent tocopherol analogues also display potent anticancer activity. Polyphenolic compounds in biological systems could easily interact with metal ions producing free radical species causing several diseases in human body. The true is that controlled production of free radicals could induce apoptosis of cancer cells. Especially vitamin E and its analogues are very active in mitochondria of cells and they are potential drugs acting against cancer cells. It is also well known that tocopherol analogues are targeting only cancer cells because they are very high redox active. Even though the above reactions are very useful there are are some drawbacks in their study. There is a lack of well-known metal -organic molecules with notable mechanism of action. In this work, we are introducing new analytical methods for the determination of those models in order to be able to monitor their metabolic pathways in biological systems and we have studied the redox mechanisms behind this action and their interaction with vanadium metal ions for possible use as anticancer drugs.Keramidas Anastasios Drouza Chryssoula Theocharis Charis Kapnissi-Christodoulou ConstantinaComplete

19F NMR for the speciation and quantification of the OH-molecules in complex matrices

A novel method for the speciation and quantification of the minor OH-molecules in complex matrices in a one pot experiment based on 19F NMR spectroscopy is demonstrated. The method exerts high resolution and sensitivity comparable with conventional methods and gives reliable results when directly applied to edible oils

Synthesis, characterization of dinuclear vanadium(III) hydroquinonate- iminodiacetate complexes

A new VIII complex (1) of 2,5-bis[N,N-bis(carboxymethyl) aminomethyl]hydroquinone (bicah6-) was synthesized by reaction of H6bicah with two equivalents of VCl3 and six equivalents of base in aqueous solution. Crystallographic characterization shows the neutral complex to have a dinuclear hydroquinonate bridged structure. The octahedral environment of vanadium is occupied by the four (N, O, O, O) donor atoms in each binding site of the ligand and two H2O oxygen atoms. Addition of 2,2-bipyridine (bipy) in the reaction mixture resulted in the synthesis of a new dinuclear VIII-μ-bicah6- complex (2) containing a bipy chelated to each vanadium center. The structure of 1 was compared with the respective dinuclear structures of the bicah6- complexes with V IVO2+ (3) and VVO2+ (4). Strong hydrogen bonds between the free, the ligated to vanadium water molecules and the carboxylate and hydroquinonate oxygen atoms result in supramolecular 3D structures by self-assembly of the dinuclear units. These structures are controlled by synthesis conditions and vanadium ion coordination environment. The cyclic voltammogram of 1 showed a reversible VIV+e -⇋VIII process at 0.48 V versus NHE. The EPR spectra of 3 gave a broad peak indicating magnetic interactions between the uncoupled electrons of the two vanadium centers through the hydroquinone bridge. In acidic pHs bellow 2.0, EPR data reveal protonation of the hydroquinonate oxygen and hydrolysis of the complex. The relation of these results with the reduction of VIV and stabilization of VIII ions is discussed

Synthesis, characterization of dinuclear vanadium(III) hydroquinonate- iminodiacetate complexes

A new VIII complex (1) of 2,5-bis[N,N-bis(carboxymethyl) aminomethyl]hydroquinone (bicah6-) was synthesized by reaction of H6bicah with two equivalents of VCl3 and six equivalents of base in aqueous solution. Crystallographic characterization shows the neutral complex to have a dinuclear hydroquinonate bridged structure. The octahedral environment of vanadium is occupied by the four (N, O, O, O) donor atoms in each binding site of the ligand and two H2O oxygen atoms. Addition of 2,2-bipyridine (bipy) in the reaction mixture resulted in the synthesis of a new dinuclear VIII-μ-bicah6- complex (2) containing a bipy chelated to each vanadium center. The structure of 1 was compared with the respective dinuclear structures of the bicah6- complexes with V IVO2+ (3) and VVO2+ (4). Strong hydrogen bonds between the free, the ligated to vanadium water molecules and the carboxylate and hydroquinonate oxygen atoms result in supramolecular 3D structures by self-assembly of the dinuclear units. These structures are controlled by synthesis conditions and vanadium ion coordination environment. The cyclic voltammogram of 1 showed a reversible VIV+e -⇋VIII process at 0.48 V versus NHE. The EPR spectra of 3 gave a broad peak indicating magnetic interactions between the uncoupled electrons of the two vanadium centers through the hydroquinone bridge. In acidic pHs bellow 2.0, EPR data reveal protonation of the hydroquinonate oxygen and hydrolysis of the complex. The relation of these results with the reduction of VIV and stabilization of VIII ions is discussed

Donor atom electrochemical contribution to redox potentials of square pyramidal vanadyl complexes

A simple donor atom additivity relationship has been used to calculate the donor atom electrochemical contribution (DEC) of the Oac (acetylacetonate-enolic oxygen), OPh (phenolic oxygen), SPh (mercaptophenol sulfur), Nam (deprotonate amide nitrogen), Nim (imine nitrogen) and Npy (pyridine nitrogen) to the redox processes of the square pyramidal vanadyl complexes. The study focuses on the amidate vanadyl complexes because of (a) their biological interest and (b) the existence of data from plethora complexes studied in great details. The electrochemical contributions for the vanadyl oxidation and reduction processes increase following the same order, OPh ~ Oac(enolic) < SPh ~ Nam < Nim < Npy. These values predict the electrochemical potentials of square pyramidal vanadyl complexes with high accuracy. Octahedral complexes with the same equatorial environment show significant shift of the oxidation potentials to lower values. The DEC influence to the square pyramidal vanadyls' electrochemical potentials has been evaluated

Binuclear VIV/V, MoVI and ZnII - hydroquinonate complexes: Synthesis, stability, oxidative activity and anticancer properties

Since the discovery of the anticancer properties of cis-platin the road for the development of less toxic and more specific metal ion based anticancer drugs has opened. Based on the low toxicity of VIV/V, MoVI and ZnII metal ions, their binuclear hydroquinonate complexes have been synthesized and their biological activity towards their anticancer properties on various cancerous and non-cancerous cell lines has been evaluated. The new complexes of ZnII with the ligands 2,5-bis((bis(pyridin-2-ylmethyl)amino)methyl)benzene-1,4-diol (H2bpymah) and 2,2'-(((2,5-dihydroxy-1,4-phenylene)bis(methylene))bis((carboxymethyl)ammoniumdiyl))diacetate (H6bicah) have been synthesized and characterized by X-ray crystallography in solid state and 1H NMR in aqueous solution. The binuclear nature of the complexes increases their hydrolytic stability in aqueous solutions at pD 7.0, depending on the metal ion. The most hydrolytic stable VV and ZnII hydroquinonate complexes show to activate O2 towards oxidation of mercaptoethanol in aqueous solutions at physiological pHs. Only the strongest oxidant, the VV complex with bicah6-, significantly activates the intracellular radical oxygen species (ROS) generation. Apparently, the mercaptoethanol oxidation experiment vs time can be used as a preliminary experiment for the prediction of the in vitro ROS generation activity of the complexes in aqueous solutions

Interaction of chromium(III) with aN,N′-disubstituted hydroxylamine-(diamido) ligand: a combined experimental and theoretical study

Reaction of hydroxylamine hydrochloride with prop-2-enamide in dichloromethane in the presence of triethylamine resulted in the isolation of the N,N′-disubstituted hydroxylamine-(diamido) ligand, 3,3′-(hydroxyazanediyl)dipropanamide (Hhydia). The ligand Hhydia was characterized by multinuclear NMR, high-resolution electrospray ionization mass spectrometry (ESI-MS), and X-ray structure analysis. Interaction of Hhydia with trans-[CrIIICl2(H2O)4]Cl·2H2O in ethanol yields the ionization isomers [CrIII(Hhydia)2]Cl3·2H2O(1·2H2O) and cis/trans-[CrIIICl2(Hhydia)2]Cl·2H2O (2·2H2O). The X-ray structure analysis of 1 revealed that the chromium atom in [CrIII(Hhydia)2]Cl·2H2O (2·2H2O). The X-ray structure analysis of 1 revealed that the chromium atom in [CrIII(Hhydia)23+ is bonded to two neutral tridentate O,N,O-Hhydia ligands. The twist angle, θ, in [CrIII(Hhydia)2]3+ is 54.5(6)0, that is, very close to an ideal octahedron. The intramolecular hydrogen bonds developed between the N–OH group of the first ligand and the amidic oxygen atom of the second ligand and vice versa contribute to the overall stability of the cation [CrIII(Hhydia)2]3+. The reaction rate constant of the formation of Cr(III) complexes 1·2H2O and 2·2H2O was found to be 8.7(±0.8) × 10–5 M–1 s–1 at 25 °C in methyl alcohol and follows a first-order law kinetics based on the biologically relevant ligand Hhydia. The reaction rate constant is considerably faster in comparison with the corresponding water exchange rate constant for the hydrated chromium(III). The modification of the kinetics is of fundamental importance for the chromium(III) chemistry in biological systems. Ultraviolet-visible and electron paramagnetic resonance studies, both in solution and in the solid state, ESI-MS, and conductivity measurements support the fact that, irrespective of the solvent used in the interaction of Hhydia with trans-[CrIIICl2(H2O)4]Cl·2H2O, the ionization isomers[CrIII(Hhydia)2]Cl3·2H2O (1·2H2O) and cis/trans-[CrIIICl2(Hhydia)2]Cl·2H2O (2·2H2O) are produced.The reaction medium affects only the relevant percentage of the isomers in the solid state. The thermodynamic stability of the ionization isomers 1·2H2O and cis/trans-2·2H2O, their molecular structures as well as the vibrational spectra and the energetics of the CrIII– Hhydia/hydia– were studied by means of density functional theory calculations and found to be in excellent agreement with our experimental observations

Synthesis of vitamin E and aliphatic lipid vanadium(IV) and (V) complexes, and their cytotoxic properties

Novel vitamin E chelate derivatives and their VIV/V complexes have been synthesized and characterized, and their anticancer properties have been evaluated. The new complexes have been designed to exhibit enhanced cytotoxicity by combining high lipophilicity with the properties of vanadium to induce the formation of reactive oxygen species (ROS). In particular, the β-tocopherol derivatives with iminodiethanol (β-tocDEA) and dipicolylamine (β-tocDPA) as well their VV and VIV complexes, [VVO(β-tocDEA] and [VIVO(β-tocDPA] have been synthesized and characterized by Nuclear Magnetic Resonance (NMR), Ultra Violet-Visible (UV–Vis) and Electron Paramagnetic Resonance (EPR) spectroscopies. Although the β-tocopherol compounds exhibit antioxidant activity their complexes induce formation of radicals. In addition, two vanadium amphiphilic complexes of 2,2′-((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) and 1-(bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) known to activate O2 and produce ROS were synthesized and characterized (C. Drouza, A. Dieronitou, I. Hadjiadamou, M. Stylianou, J. Agric. Food. Chem., vol. 65, 2017, pp. 4942–4951). The four amphiphilic vanadium complexes exhibit enhanced hydrolytic stability. All compounds found to be cytotoxic for cancer cells exhibiting activity similar or higher to cis-platin

Interaction of Chromium(III) with a <i>N</i>,<i>N</i>′‑Disubstituted Hydroxylamine-(diamido) Ligand: A Combined Experimental and Theoretical Study

Reaction of hydroxylamine hydrochloride with prop-2-enamide in dichloromethane in the presence of triethylamine resulted in the isolation of the <i>N</i>,<i>N</i>′-disubstituted hydroxylamine-(diamido) ligand, 3,3′-(hydroxyazanediyl)­dipropanamide (Hhydia). The ligand Hhydia was characterized by multinuclear NMR, high-resolution electrospray ionization mass spectrometry (ESI-MS), and X-ray structure analysis. Interaction of Hhydia with <i>trans</i>-[Cr^IIICl₂(H₂O)₄]­Cl·2H₂O in ethanol yields the ionization isomers [Cr^III(Hhydia)₂]­Cl₃·2H₂O­(<b>1</b>·2H₂O) and <i>cis/trans-</i>[Cr^IIICl₂(Hhydia)₂]­Cl·2H₂O (<b>2</b>·2H₂O). The X-ray structure analysis of <b>1</b> revealed that the chromium atom in [Cr^III(Hhydia)₂]³⁺ is bonded to two neutral tridentate <i>O</i>,<i>N</i>,<i>O</i>-Hhydia ligands. The twist angle, <i>θ,</i> in [Cr^III(Hhydia)₂]³⁺ is 54.5(6)⁰, that is, very close to an ideal octahedron. The intramolecular hydrogen bonds developed between the N–OH group of the first ligand and the amidic oxygen atom of the second ligand and vice versa contribute to the overall stability of the cation [Cr^III(Hhydia)₂]³⁺. The reaction rate constant of the formation of Cr­(III) complexes <b>1</b>·2H₂O and <b>2</b>·2H₂O was found to be 8.7(±0.8) × 10^–5 M^–1 s^–1 at 25 °C in methyl alcohol and follows a first-order law kinetics based on the biologically relevant ligand Hhydia. The reaction rate constant is considerably faster in comparison with the corresponding water exchange rate constant for the hydrated chromium­(III). The modification of the kinetics is of fundamental importance for the chromium­(III) chemistry in biological systems. Ultraviolet-visible and electron paramagnetic resonance studies, both in solution and in the solid state, ESI-MS, and conductivity measurements support the fact that, irrespective of the solvent used in the interaction of Hhydia with <i>trans</i>-[Cr^IIICl₂(H₂O)₄]­Cl·2H₂O, the ionization isomers­[Cr^III(Hhydia)₂]­Cl₃·2H₂O (<b>1</b>·2H₂O) and <i>cis/trans-</i>[Cr^IIICl₂(Hhydia)₂]­Cl·2H₂O (<b>2</b>·2H₂O) are produced.The reaction medium affects only the relevant percentage of the isomers in the solid state. The thermodynamic stability of the ionization isomers <b>1</b>·2H₂O and <i>cis/trans-</i><b>2</b>·2H₂O, their molecular structures as well as the vibrational spectra and the energetics of the Cr^III– Hhydia/hydia^– were studied by means of density functional theory calculations and found to be in excellent agreement with our experimental observations