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Domotor O.,University of Szeged | Tuccinardi T.,University of Pisa | Karcz D.,Jagiellonian University | Walsh M.,Institute of Technology Tallaght | And 3 more authors.
Bioorganic Chemistry | Year: 2014

The specific binding of five reduced Schiff base derived 7-amino-coumarin compounds with antitumor activity to human serum albumin, the principal binding protein of blood, was studied by fluorescence spectroscopy. Their conditional binding constants were computed and the reversible binding at the Sudlow's site I was found to be strong (KD ∼ 0.03-2.09 μM). Based on the data albumin can provide a depot for the compounds and is responsible for their biodistribution and transport processes. The experimental data is complemented by protein-ligand docking calculations for two representatives which support the observations. The proton dissociation constants of the compounds were also determined by UV-Vis spectrophotometric and fluorometric titrations to obtain the actual charges and distribution of the species in the various protonation states at physiological pH. © 2013 Elsevier Inc. All rights reserved.

Sija E.,HAS USZ Bioinorganic Chemistry Research Group | Nagy N.V.,Institute of Molecular Pharmacology | Gandin V.,University of Padua | Marzano C.,University of Padua | And 5 more authors.
Polyhedron | Year: 2014

The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4-hydroxy-3-pyridinecarboxylic acid (DQ715) and Cu(II) and Zn(II) were investigated with the aim to restore the homeostasis of the brain Cu(II) and Zn(II) in neurodegenerative diseases. The proton dissociation constants of the ligands, the stability constants, and the coordination modes of the metal complexes formed were determined by pH-potentiometric, and spectral (UV-Vis and EPR or 1H NMR) methods. The results show that in slightly acidic and neutral pH range mono and bis complexes are formed through bidentate coordination of the ligands. The biological MTT-test reveals that the DQ715 ligand is able to lower the cytotoxic effect of Cu(II) in human embryonic kidney HEK-293 cells. Our studies revealed, however, that none of the chelators were efficient enough to withdraw these metal ions from the amyloid aggregates. © 2013 Elsevier Ltd. All rights reserved.

Bacher F.,University of Vienna | Enyedy E.A.,University of Szeged | Nagy N.V.,Hungarian Academy of Sciences | Rockenbauer A.,Hungarian Academy of Sciences | And 7 more authors.
Inorganic Chemistry | Year: 2013

Two proline-thiosemicarbazone bioconjugates with excellent aqueous solubility, namely, 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [l-Pro-FTSC or (S)-H2L] and 3-methyl-(R)- pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone [d-Pro-FTSC or (R)-H2L], have been synthesized and characterized by elemental analysis, one- and two-dimensional 1H and 13C NMR spectroscopy, and electrospray ionization mass spectrometry. The complexation behavior of l-Pro-FTSC with copper(II) in an aqueous solution and in a 30% (w/w) dimethyl sulfoxide/water mixture has been studied via pH potentiometry, UV-vis spectrophotometry, electron paramagnetic resonance, 1H NMR spectroscopy, and spectrofluorimetry. By the reaction of copper(II) acetate with (S)-H2L and (R)-H2L in water, the complexes [Cu(S,R)-L] and [Cu(R,S)-L] have been synthesized and comprehensively characterized. An X-ray diffraction study of [Cu(S,R)-L] showed the formation of a square-pyramidal complex, with the bioconjugate acting as a pentadentate ligand. Both copper(II) complexes displayed antiproliferative activity in CH1 ovarian carcinoma cells and inhibited Topoisomerase IIα activity in a DNA plasmid relaxation assay. © 2013 American Chemical Society.

Primik M.F.,University of Vienna | Goschl S.,University of Vienna | Meier S.M.,University of Vienna | Eberherr N.,University of Vienna | And 5 more authors.
Inorganic Chemistry | Year: 2013

Dicopper(II) and dizinc(II) complexes [Cu2( MeOOCLCOO)(CH3COO)2] (1) and [Zn2(MeOOCLCOO)(CH3COO) 2] (2) were synthesized by reaction of Cu(CH3COO) 2·H2O and Zn(CH3COO)2· 2H2O with a new nonsymmetric dinucleating ligand EtOOCHLCOOEt prepared by condensation of 6-hydrazinyl-11H-indolo[3,2-c]quinoline with diethyl-2,2'-((3-formyl-2-hydroxy- 5-methylbenzyl)azanediyl)diacetate. The design and synthesis of this elaborate ligand was performed with the aim of increasing the aqueous solubility of indolo[3,2-c]quinolines, known as biologically active compounds, and investigating the antiproliferative activity in human cancer cell lines and the cellular distribution by exploring the intrinsic fluorescence of the indoloquinoline scaffold. The compounds have been comprehensively characterized by elemental analysis, spectroscopic methods (IR, UV-vis, 1H and 13C NMR spectroscopy), ESI mass spectrometry, magnetic susceptibility measurements, and UV-vis complex formation studies (for 1) as well as by X-ray crystallography (1 and 2). The antiproliferative activity of EtOOCHLCOOEt, 1, and 2 was determined by the MTT assay in three human cancer cell lines, namely, A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma), yielding IC50 values in the micromolar concentration range and showing dependence on the cell line. The effect of metal coordination on cytotoxicity of EtOOCHLCOOEt is also discussed. The subcellular distribution of EtOOCHLCOOEt and 2 was investigated by fluorescence microscopy, revealing similar localization for both compounds in cytoplasmic structures. © 2013 American Chemical Society.

Sija E.,University of Szeged | Sija E.,HAS USZ Bioinorganic Chemistry Research Group | Hartinger C.G.,University of Auckland | Hartinger C.G.,University of Vienna | And 4 more authors.
Polyhedron | Year: 2014

Stoichiometry and stability of antitumor ruthenium(II)-η6-p- cymene complexes of picolinic acid and its 6-methyl and 6-carboxylic acid derivatives were determined by pH-potentiometry, 1H NMR spectroscopy and UV-Vis spectrophotometry in aqueous solution in the presence or absence of coordinating chloride ions. The picolinates form exclusively mono-ligand complexes in which they can coordinate via the bidentate (O,N) mode and a chloride or a water molecule is found at the third binding site of the ruthenium(II)-η6-p-cymene moiety depending on the conditions. [Ru(η6-p-cymene)(L)(H2O/Cl)] species are predominant at physiological pH in all studied cases. Hydrolysis of the aqua complex or the chlorido/hydroxido co-ligand exchange results in the formation of the mixed-hydroxido species [Ru(η6-p-cymene)(L)(OH)] in the basic pH range. There is no indication for the decomposition of the mono-ligand complexes during 24 h in the ruthenium(II)-η6-p-cymene-picolinic acid system between pH 3 and 11; however, a slight dissociation with a low reaction rate was found in the other two systems leading to the appearance of the dinuclear trihydroxido-bridged species [Ru2(η6-p- cymene)2(OH)3]+ and free ligands at pH > 10. The replacement of the chlorido by an aqua ligand in [Ru(η6-p- cymene)(L)Cl] was also monitored and equilibrium constants for the exchange process were determined. © 2013 Elsevier Ltd. All rights reserved.

Jakusch T.,University of Szeged | Enyedy E.A.,University of Szeged | Kozma K.,University of Szeged | Paar Z.,University of Szeged | And 3 more authors.
Inorganica Chimica Acta | Year: 2014

Several articles were published about the vanadate-3-hydroxy-1,2-dimethyl- pyridinone (Hdhp) system, however, the results are contradictory and not complete: pH-potentiometry and 51V NMR spectroscopy were used to clarify this complicated system. The eleven peaks in the spectra at different chemical shifts were assigned to ten stoichiometrically different compounds; four of them are new, never identified or assigned before. Besides the simple mono (in two different protonation states) and bis complexes (in three different protonation states) a tris complex, three dinuclear and a trinuclear complex were found based on the 51V NMR spectra measured at different pH values and various metal ion concentrations and metal-to-ligand ratios. As a joint evaluation of the two methods, overall stability constants were calculated for all species. X-ray structure of the potassium salt of the bis complex, [V(V)O2(dhp)2]- was also determined. The trans effect of the oxido-oxygens results in maltolato-type coordination of the ligand instead of the catecholate-like chelation. The redox properties of [V(V)O 2(dhp)2]- and some other prodrug vanadium(V) bis complexes were investigated by spectrophotometry in aqueous solution via their reduction by glutathione (GSH) and l-ascorbic acid (ASC) under strictly anaerobic conditions and by cyclic voltammetry at physiological pH. The reduction was found to be much faster by ASC in all cases as compared with GSH and the reaction rate of the reduction of [V(V)O2(dhp) 2]- was prominently high most probably due to the formation of the significantly higher stability of the corresponding vanadium(IV) complex. © 2014 Elsevier B.V. All rights reserved.

Enyedy E.A.,University of Szeged | Bognar G.M.,University of Szeged | Nagy N.V.,Hungarian Academy of Sciences | Jakusch T.,University of Szeged | And 3 more authors.
Polyhedron | Year: 2014

The stoichiometry and thermodynamic stability of copper(II), vanadium(IV/V), iron(II)/(III) and gallium(III) complexes of salicylaldehyde semicarbazone (SSC, HL) and its 5-bromo derivative (Br-SSC, HL) have been determined by pH-potentiometry, UV-Vis spectrophotometry, EPR, 1H and 51V NMR spectroscopy in 30% (w/w) dimethyl sulfoxide/water solvent mixture. Proton dissociation processes and lipophilicity of the ligands were also studied in detail. Formation of mono-ligand complexes such as [ML], [MLH-1], [MLH-2] was found with copper(II), vanadium(IV/V), while bis-ligand species of iron(II)/(III) and gallium(III) such as [ML2], [ML2H-1] and [ML2H -2] were also detected, in which the ligands coordinate via monoanionic (O-,N1,O) or dianionic (O-,N 1,O-) modes. The bromine substituent on the phenol ring has no significant impact on the stability and binding modes but provides a remarkably enhanced lipophilic character, which is advantageous for the bioactivity. The Ga(III)-salicylaldehyde semicarbazone species show unambiguously higher stability; whereas Cu(II) species have somewhat lower stability relative to the corresponding thiosemicarbazone analogues, however no decomposition of the Cu(II) complex was observed even at micromolar concentrations at physiological pH. © 2013 Elsevier Ltd. All rights reserved.

Jakusch T.,University of Szeged | Kiss T.,University of Szeged | Kiss T.,HAS USZ Bioinorganic Chemistry Research Group
Zeitschrift fur Anorganische und Allgemeine Chemie | Year: 2013

Speciations of ruthenium(III)-edta complexes of bidentate (O, O) (N, O) and (S, O) donor type ligands were determined by pH-potentiometry and UV/Vis spectrophotometry in aqueous solution. Complexes of [RuIII(edtaH x)L]2- (x = 0, 1, 2 and 3) stoichiometry were only formed and the fully deprotonated species dominate at the physiological pH 7.4. Protonation occurs at the free carboxylate arms of edta; when x = 3 one of the coordination positions of the RuIII becomes free. Formation of protonated ternary complexes are more characteristic for ligands with (N, O) and (S, O) donor sets where the complex formation started (ligands with (N, O) donor set) or completed (ligands with (S, O) donor set) already at pH 2. In acidic conditions the stability order of the complexes follows the (O, O) < (N, O) < (S, O) sequence, which changes slightly for the physiological pH 7.4: (O, O) ≈ (N, O) < (S, O). The complexes formed were characterised also by LNT EPR spectroscopy. The kinetics of the ligand exchange between ternary complexes at pH 6 was found to be dissociative. The reaction rate follows basically the stability order: (O, O) < (N, O) < (S, O). No side reactions were found when the ligands replaced had (O, O) donor set; but formation of [RuIII(edta)(L1),(L2)] 3- was hypothesised in the case of ligands with (N, O) or (S, O) donor sets. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Kiss T.,University of Szeged | Kiss T.,HAS USZ Bioinorganic Chemistry Research Group
Journal of Inorganic Biochemistry | Year: 2013

The paper gives a review on the importance of distribution of Al in biological fluids, primarily in the lights of the works of the author in Al chemistry. It starts with studies of interactions of Al(III) with small biomolecules, such as aliphatic and aromatic hydroxycarboxylic acids, and inorganic and organic phosphates. A significant part of this review deals with the problems of description of the biospeciation of Al(III) in serum, where besides the thermodynamic conditions the role of time is also considered in the case of this sluggish metal ion. The Al(III) complexes of the other large group of biomolecules, proteins and their building blocks (oligo)peptides and amino acids are also discussed, where the role of the type of the side chain donors and the extent of preorganisation are considered in the efficiency of metal ion binding. The application of low molecular mass chelator molecules in restoring the dysfunctioning metal ion (including Al(III)) homeostasis in the treatment of Alzheimer's disease is also discussed in the paper. © 2013 Elsevier Inc.

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