Tamás Kiss - Academia.edu (original) (raw)

Papers by Tamás Kiss

Inorganic chemistry, Jan 18, 2018

British anti-Lewisite (2,3-dimerkaptopropan-1-ol, dimercaprol, BAL) is one of the best-known chel... more British anti-Lewisite (2,3-dimerkaptopropan-1-ol, dimercaprol, BAL) is one of the best-known chelator-type therapeutic agents against toxic metal ions and metalloids, especially arsenicals. Surprisingly, the mechanisms of action at the molecular level, as well as the coordination features of this traditional drug toward various arsenicals, are still poorly revealed. The present study on the interaction of arsenous acid (HAsO) with BAL, involving UV and NMR titrations, electrospray ionization mass spectrometry, and 2D NMR experiments combined with MP2 calculations, demonstrates that the reaction of HAsO with BAL at pH = 7.0 results in a more complex speciation than was assumed before. The three reactive hydroxyl groups of HAsO allow for interaction with three thiol moieties via condensation reaction, leading to the observed AsBAL and AsBAL complexes besides the AsBAL species. This indicates the strong propensity of inorganic As(III) to saturate its coordination sphere with thiolate g...

Current medicinal chemistry, Jan 6, 2018

Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal act... more Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids.

Inorganica Chimica Acta, 2017

The stoichiometry and thermodynamic stability of vanadium IV/V and copper II complexes of pyridox... more The stoichiometry and thermodynamic stability of vanadium IV/V and copper II complexes of pyridoxal thiosemicarbazone and pyridoxal-N 3 ,N 3-dimethylthiosemicarbazone have been determined by pH-potentiometry (V IV O), EPR (V IV O/Cu II), UV-Vis (Cu II , V IV O and V V) and 51 V-NMR spectroscopy (V V) in 30% (w/w) dimethyl sulfoxide/water solvent mixture. In all cases, mono-ligand complexes are formed in different protonation states. In addition, the proton-dissociation constants of the ligands were also determined by pH-potentiometry, UV-Vis and 1 H-NMR spectroscopy. The solid state structures of the monoprotonated forms (V V O 2 (L 1 H)×0.8H 2 O and V V O 2 (L 2 H)×0.8H 2 O) of the V V complexes were characterized by single-crystal X-ray diffraction analysis. The mono-ligand complexes of Cu II and V V are dominant at physiological pH. With all investigated metal ions the pyridoxal moiety of the ligand causes an extra deprotonation step between pH 4 and 7 due to the non-coordinating pyridine-NH +. The pyridoxal-containing ligands form somewhat more stable complexes with both V IV O and Cu II ions than the reference compound salicylaldehyde thiosemicarbazone. Dimethylation of the terminal amino group resulted in the formation of V V and Cu II complexes with even higher stability.

Coordination Chemistry Reviews, 2017

The paper deals with the so far most efficient antidiabetic transition metal compound family. It ... more The paper deals with the so far most efficient antidiabetic transition metal compound family. It focuses on the species distribution of the most frequently studied vanadium(IV,V) compounds in biology: in the gastro-intestinal tract (being important in absorption of the compounds), the blood serum (very likely the main route of their transport), the whole blood (recently the role of the red blood cells are also assumed in their transport) and in the cells (where glutathione and ATP may be the most important redox and complex formation partners of the original vanadium-"insulinomimetics"). The discussed details fit into the general view, but far from a complete and clear understanding of the pharmacodynamics of these antidiabetics. A lot more in vitro and mostly in vivo studies are necessary to justify their real clinical use. Contents 2.4. Speciation of vanadium with high molecular mass (HMM) constituents of blood serum 2.5 Speciation of vanadium(IV) and vanadium(V) in blood serum 2.6. Interactions of vanadium in the whole blood 2.7. Speciation of vanadium in the cells 3. Conclusions Acknowledgements References Abbreviations: GI, gastrointestinal; LMM, low molecular mass; HMM, high molecular mass; HIV, human immunodeficiency virus; DM, diabetes mellitus; STZ, streptozotocin; BMOV, bis(maltolato)oxovanadium(IV); BEOV, bis(ethylmaltolato)oxovanadium(IV); acac, acetylacetone; mal, maltol (3-hydroxy-2-methyl-4-pyrone); imal, isomaltol [1-(3-hydroxy-2furanyl) ethanone]; amal, allomaltol (3-hydroxy-6-methyl-4-pyrone); emal, ethyl maltol (3hydroxy-2-ethyl-4-pyrone); ipmal, isopropyl maltol (3-hydroxy-2-isopropyl-4-pyrone); alx, allixin (3-hydroxy-5-methoxy-6-methyl-2-pentyl-4-pyrone); koj, kojic acid [5-Hydroxy-2-(hydroxymethyl)-4-pyrone]; cur, curcumin; hpno, 2-hydroxypyridine N-oxide; dhp, 3hydroxy-1,2-dimethyl-4(1H)-pyridone; hopy, 1-hydroxy-2(1H)-pyrimidone; dmhopy, 1hydroxy-4,6-dimethyl-2(1H)-pyrimidone; mhopy, 1-hydroxy-6-methyl-2(1H)-pyrimidone; pic, picolinic acid; 6mpic, 6-methylpicolinic acid; 6etpic, 6-ethylpicolinic acid; 5ipic, 5iodopicolinic acid; 3mpic, 3-methylpicolinic acid; 3hpic, 3-hydroxypicolinic acid; dipic, 2,6dipicolinic acid; biguad, biguanide; metf, metformin (N',N'-dimethylbiguanide); mpno, 2mercaptopyridine N-oxide; ROS, reactive oxygen species; XANES, X-ray absorption near edge structure; Tf, transferrin(human); apoTf, apotransferrin(human); HSA, human serum transferrin; his, histidine; asp, aspartic acid; tyr, tyrosine; gly, glycine; NTS, N-terminal (binding) site; ATCUN, amino terminal Cu(II)-and Ni(II)-binding; MBS, multiple binding sites; IgG, immunoglobulin G; EPR, electron paramagnetic resonance; CD, circular dichroism; ICP-MS, inductively coupled plasma mass spectrometry; LC50, lethal concentration 50%; Hb, hemoglobin; RBC, red blood cell; GSH, glutathione; GSSG,

Journal of inorganic biochemistry, Mar 14, 2016

Two recently published Ru(III) complexes bearing (N2O2) tetradentate bis(aminophenolate) ligands,... more Two recently published Ru(III) complexes bearing (N2O2) tetradentate bis(aminophenolate) ligands, formulated as [Ru(III)(salan)(PPh3)Cl] (salan is the tetradentate ligand 6,6'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol) in complex 1, or 2,2'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol) in complex 2; PPh3 is triphenylphosphane) and found very active against ovarian and breast adenocarcinoma human cells were studied to outline their antitumor mode of action. The human cisplatin-sensitive ovarian adenocarcinoma line A2780 was used herein as the cell model. At a 24h challenge (similarly as found before for 72h) both complexes are active, their cytotoxicity being comparable to that of cisplatin in the same conditions. As a possible target in the cell for their action, the interaction of 1 and 2 with DNA was assessed through displacement of well-established DNA fluorescent probes (ethidium bromide, EB, and 4',6-d...

A támogatott kutatási projekt céljai (a) Réz-, kobalt-és vasionok aminosav komplexeinek (L-hiszti... more A támogatott kutatási projekt céljai (a) Réz-, kobalt-és vasionok aminosav komplexeinek (L-hisztidin, L-tirozin-és Lcisztein) elkészítése és rögzítése különféle hordozókon többféle módszerrel. (b) A katalizátorok jellemzése, és aktivitásuk/szelektivitásuk tesztelése egyszerű oxidációs/dizmutációs és összetettebb szerves kémiai oxidációs reakciókban. (c) A katalizátorok és a reakciók modellezése kvantumkémiai módszerekkel. A kutatások menete és az elért eredmények A kutatás kezdő évében (2006) különféle réz-tirozin és réz-hisztidin komplexek kovalens immobilizálására került sor. A szintézisek kézbentartásának érdekében C-illetve N-terminálison védett aminosavakkal dolgoztunk. Hordozóként használtunk klórpropilezett szilikagélt és klórozott polisztirolt egyaránt. Szilikagél használatakor a komplexek kialakítására a védőcsoport eltávolítása után került sor, azaz a heterogenizált komplex ligandumjai (tirozin vagy hisztidin) védőcsoport nélküli aminosavak voltak. A gyanta használatakor a rézkomplex kialakítása a védett ligandumokkal történt. A kapott heterogenizált komplexeket infravörös spektroszkópiával jellemeztük. Egyéb analitikai módszerekkel (atomabszorpciós spektroszkópia, Kjeldahl-módszer) meghatároztuk a koordinációs számot, és a feltételezett szerkezeteket modelleztük is (MM+ kód). A szilikagélen kialakított komplexek kataláz-aktivitását teszteltük, és, meglepetésünkre, tirozináz-aktivitást is találtunk, amikor a ligandum a tirozin volt. Kapott eredményeinket két közleményben foglaltuk össze [Jakab, I.N., Szabó, É., Hernadi, K., Pálinkó, I.: The synthesis and the catalytic (catalase and tyrosinase) activities of amino acid copper complexes covalently grafted onto silica gel, Sampling

Polyhedron, 2014

The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4hydr... more The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4hydroxy-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 dissoci ation constants o f 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 o f Cu(II) in human embryonic kidney HEK-293 cells. Our studies revealed, how ever, that none of the chelators were efficient enough to withdraw these metal ions from the amyloid aggregates.

Journal of Pharmaceutical and Biomedical Analysis, 2011

The lipophilic character of several carrier ligands of antidiabetic Zn(II) and VO(IV) metal compl... more The lipophilic character of several carrier ligands of antidiabetic Zn(II) and VO(IV) metal complexes were characterized by the traditional saturation shake flask method based on n-octanol/water partitioning. The transfer of the neutral ligand species to the organic phase was followed by UV spectrophotometry at various pH and the partition and distribution coefficients were calculated with the help of the proton dissociation constants and the spectra of the individual ligand species. Partition and distribution coefficients of the Zn(II) and VO(IV) complexes were determined by analysis of the metal ion content of the aqueous phases before and after separation by ICP-AES, their UV spectra and the corresponding concentration distribution curves. Results revealed the fairly hydrophilic character both the carrier ligands and their neutral Zn(II) and VO(IV) complexes. A quasi-linear relationship was found between logP of the ligands and that of the metal species in the case of the ligands studied with the exception of the picolinates. Importance of the knowledge of the chemical speciation (i.e. stoichiometry and stability constants) was also highlighted for the characterization of the lipophilic character of the kinetically labile metal complexes.

Journal of Inorganic Biochemistry, 2013

Stoichiometry and stability of antitumor ruthenium(II)−η 6-p-cymene complexes of bidentate (O,O) ... more Stoichiometry and stability of antitumor ruthenium(II)−η 6-p-cymene complexes of bidentate (O,O) hydroxypyrone and (O,S) hydroxythiopyr(id)one type ligands were determined by pHpotentiometry, 1 H NMR spectroscopy and UV−Vis spectrophotometry in aqueous solution and in dependence of chloride ion concentration. Formation of mono-ligand complexes with moderate stability was found in the case of the hydroxypyrone ligands (ethyl maltol and allomaltol) predominating at the physiological pH range. These complexes decompose to the dinuclear tri-hydroxido bridged species [{Ru II (η 6-p-cymene} 2 (OH) 3 ] and to the metal-free ligand at basic pH values. In addition, formation of a hydroxido [Ru II (η 6-p-cymene)(L)(OH)] species was found. The hydroxythiopyr(id)one ligands (thiomaltol, thioallomaltol, 3-hydroxy-1,2-dimethyl-thiopyridone) form complexes of significantly higher stability compared with the hydroxypyrones; their complexes are biologically more active, the simultaneous bi-and monodentate coordination of the ligands in the bis complexes (ML 2 and ML 2 H) was also demonstrated. In the case of thiomaltol, formation of tris complexes is also likely at high pH. The replacement of the chlorido by the aqua ligand in the [Ru II (η 6-p-cymene)(L)(Cl)] species was monitored, which is an important activation step in the course of the mode of action of the complexes, facilitating binding to biological targets.

Dalton Transactions, 2009

The interactions of various insulin mimetic oxovanadium(IV) compounds with serum proteins were st... more The interactions of various insulin mimetic oxovanadium(IV) compounds with serum proteins were studied in model systems and in ex vivo samples. For the modeling study, an earlier in situ method was extended and applied to the formation of ternary complexes of apotransferrin (apoTf)-V(IV)O-maltol (mal) and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone (dhp). Both systems were evaluated via simultaneous CD and EPR measurements. Determination of the formation constants of the ternary complexes allowed the calculation of more accurate stability constants for the V(IV)O-apoTf parent complexes and establishment of a better model for drug speciation in serum. It was found that dhp and the synergistic carbonate are non-competitive binders. Based on the stability constants obtained for V(IV)O-apoTf complexes and estimated for V(IV)O-HSA (= human serum albumin), modeling calculations were performed on the distribution of V(IV)O among the components of blood serum. The results were confirmed by HPLC-ICP-MS (liquid chromatography-inductively coupled plasma spectroscopy-mass spectrometry) measurements. The ex vivo interactions of the V(IV)O complexes formed with mal, picolinic acid (pic) and dhp with serum protein standards and also with human serum samples were evaluated. The proteins were firstly separated by (HPLC), and the V content of each fraction was determined by ICP-MS. All the studied V(IV)O compounds displayed similar chromatographic profiles, associated almost exclusively with apotransferrin as predicted by the modeling calculations. Under physiological conditions, the interactions with HSA of all of the species under study were negligible. Therefore Tf seems to be the main V(IV)O transporter in the serum under in vitro conditions, and this association is practically independent of the chemical form in which V(IV)O is administered.

Dalton Trans., 2012

Figure S1. Molar absorption spectra of the Cu(II) complexes formed with (GH) 2 K (a) and (HH) 2 K... more Figure S1. Molar absorption spectra of the Cu(II) complexes formed with (GH) 2 K (a) and (HH) 2 K (b).

Chemistry - A European Journal, 2004

The Schiff base N,N'-ethylenebis(pyridoxylideneiminato) (H 2 pyr 2 en, 1) was synthesized by reac... more The Schiff base N,N'-ethylenebis(pyridoxylideneiminato) (H 2 pyr 2 en, 1) was synthesized by reaction of pyridoxal with ethylenediamine; reduction of H 2 pyr 2 en with NaBH 4 yielded the reduced Schiff base N,N'-ethylenebis-(pyridoxylaminato) (H 2 Rpyr 2 en, 2); their crystal structures were determined by X-ray diffraction. The totally protonated forms of 1 and 2 correspond to H 6 L 4 + , and all protonation constants were determined by pH-potentiometric and 1 H NMR titrations. Several vanadium(iv) and vanadium(v) complexes of these and other related ligands were prepared and characterized in solution and in the solid state. The X-ray crystal structure of [V V O 2 (HRpyr 2 en)] shows the metal in a distorted octahedral geometry, with the ligand coordinated through the N-amine and O-phenolato moieties, with one of the pyridine-N atoms protonated. Crystals of [(V V O 2) 2 (pyren) 2 ]¥2 H 2 O were obtained from solutions containing H 2 pyr 2 en and oxovanadium(iv), where Hpyren is the ™half∫ Schiff base of pyridoxal and ethylenediamine. The complexation of V IV O 2 + and V V O 2 + with H 2 pyr 2 en, H 2 Rpyr 2 en and pyridoxamine in aqueous solution were studied by pH-potentiometry, UV/Vis absorption spectrophotometry, as well as by EPR spectroscopy for the V IV O systems and 1 H and 51 V NMR spectroscopy for the V V O 2 systems. Very significant differences in the metal-binding abilities of the ligands were found. Both 1 and 2 act as tetradentate ligands. H 2 Rpyr 2 en is stable to hydrolysis and several isomers form in solution, namely cis±trans type complexes with V IV O, and a-cis-and b-cis-type complexes with V V O 2. The pyridinium-N atoms of the pyridoxal rings do not take part in the coordination but are involved in acid±base reactions that affect the number, type, and relative amount of the isomers of the V IV O± H 2 Rpyr 2 en and V V O 2 ±H 2 Rpyr 2 en complexes present in solution. DFT calculations were carried out and support the formation and identification of the isomers detected by EPR or NMR spectroscopy, and the strong equatorial and axial binding of the O-phenolato in V IV O and V V O 2 complexes. Moreover, the DFT calculations done for the [V IV O(H 2 Rpyr 2 en)] system indicate that for almost all complexes the presence of a sixth equatorial or axial H 2 O ligand leads to much more stable compounds.

Open Chemistry, 2006

An imidazolate-bridged copper(II)-zinc(II) complex (Cu(II)-diethylenetriamino-μ-imidazolato-Zn(II... more An imidazolate-bridged copper(II)-zinc(II) complex (Cu(II)-diethylenetriamino-μ-imidazolato-Zn(II)-tris(2-aminoethyl)amine perchlorate (denoted as “Cu,Zn complex”) and a simple copper(II) complex (Cu(II)-tris(2-aminoethyl) amine chloride (“Cu-tren”) were prepared and immobilised on silica gel (by hydrogen or covalent bonds) and montmorillonite (by ion exchange). The immobilised substances were characterised by FT-IR spectroscopy and their thermal characteristics were also studied. The obtained materials were tested in two probe reactions: catalytic oxidation of 3,5-di-tert-butyl catechol (DTBC) (catecholase activity) and the decomposition of hydrogen peroxide (catalase activity). It was found that the catecholase activity of the Cu,Zn complex increased considerably upon immobilization on silica gel via hydrogen bonds and intercalation by ion exchange among the layers of montmorillonite. The imidazolate-bridged copper(II)-zinc(II) complex and its immobilised versions were inactive in...

Bioorganic & Medicinal Chemistry, 2011

The specific binding of carrier ligands of antidiabetic vanadium(IV) and zinc(II) complexes into ... more The specific binding of carrier ligands of antidiabetic vanadium(IV) and zinc(II) complexes into drug binding pockets of human serum albumin (HSA) has been investigated via displacement reactions of site markers such as warfarin and dansylglycine by different spectroscopic (fluorescence, circular dichroism, NMR) and separation methods (capillary zone electrophoresis, ultrafiltration-UV). Conditional stability constants of the ligands were calculated for the binding at sites I and II of HSA. Binding site I was found to be the primary binding site for 2,6-pyridine dicarboxylic acid (dipic) and picolinic acid (pic), and site II for 6-methylpicolinic acid (6-Mepic) and maltol, although dipic, 6-Mepic and pic displace both site markers at differing extents. The experimental data is complemented by protein-ligand docking calculations for dipic and 6-Mepic which support the observations.

Biochemical and Biophysical Research Communications, 2006

Previously, we reported that intraperitoneal injections of the Zn(II) complex (Zn(alx) 2) with al... more Previously, we reported that intraperitoneal injections of the Zn(II) complex (Zn(alx) 2) with allixin, which is isolated from dry garlic, with a Zn(O 4) coordination environment, exhibited high anti-diabetic effects in obesity-linked type 2 diabetic KKA y mice. However, this complex exhibited low activity when administered orally. To improve the effect of Zn(alx) 2 , we prepared a novel Zn(II) complex with the allixin-derivative bis(1,6-dimethyl-3-hydroxy-5-methoxy-2-pentyl-1,4-dihydropyridine-4-thionato)Zn(II), abbreviated as Zn(II)-thioallixin-N-methyl (Zn(tanm) 2), having a Zn(S 2 O 2) coordination environment; this complex has extremely high in vitro insulin-like activity. Because Zn was extensively absorbed from the gastrointestinal tract when Zn(tanm) 2 was orally administered, its anti-diabetic effects were examined in KKA y mice. Daily oral administrations of Zn(tanm) 2 for 4 weeks in KKA y mice significantly improved hyperglycemia, glucose intolerance, insulin resistance, hyperleptinemia, obesity, and hypertension. Interestingly, Zn(tanm) 2 increased depressed plasma adiponectin levels in the mice. Here, we propose that Zn(tanm) 2 will be an orally active therapeutic for obesity-linked type 2 diabetes and metabolic syndromes.

Coordination Chemistry Reviews, 2017

This review provides definitions and examples of chemical speciation, as well as giving details o... more This review provides definitions and examples of chemical speciation, as well as giving details of the differences in speciation between labile and inert systems. By moving from the simple to the complex, starting with simple species distribution calculation methods based on solution structural studies, this review progresses to modeling calculations that are applicable to "real-world" systems. The biological and or medicinal speciation of the following metal ions are discussed (modeling and experimental confirmation of the calculation results as well as kinetic aspects of their changes in speciation): Al(III), Fe(III), Ga(III), Gd(III), Ru(III), Ca(II), Cu(II), Pd(II), V(IV)O, V(V), and Zn(II)). Brief introductions are also given to trace analytical and environmental speciation. The current status and future possibilities of speciation studies (evaluation and prediction of speciation data), data collection, and databases are also critically discussed.

Journal of Organometallic Chemistry, 2013

Ru II ( 6-p-cymene) complexes of two bidentate (O,O) alkoxycarbonylmethyl-3-hydroxy-2(1H)-pyrido... more Ru II ( 6-p-cymene) complexes of two bidentate (O,O) alkoxycarbonylmethyl-3-hydroxy-2(1H)-pyridone ligands exhibit in vitro antitumor activity. We determined their stoichiometry and stability in aqueous solution by pH-potentiometry, 1 H NMR spectroscopy and UV-Vis spectrophotometry and also characterized the proton dissociation processes of the ligands. Formation of mono-ligand complexes with moderate stability was found to predominate in the physiological pH range. Moreover, the chlorido/aqua co-ligand exchange processes of the [Ru II ( 6-p-cymene)(L)(H 2 O)] + species were also monitored and 55-65% of the aqua ligand was found to be replaced by chloride in 0.2 M KCl containing aqueous solutions. Under basic conditions, the complexes decompose to dinuclear tri-hydroxido-bridged [Ru  ( 6-pcymene) 2 (OH) 3 ] + and metal-free ligand and also a hydroxido species [Ru II ( 6-pcymene)(L)(OH)] was found. Furthermore, the ligands contain an ester functional group, which may hydrolyze at basic pH, which is however negligible at acidic or neutral pH.

Journal of Inorganic Biochemistry, 2011

Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the ... more Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the oxidovanadium(V) oxido-bridged dimer [{(papy)(VO)}(2) μ-O)] (1). Similarly, reaction of N-(2-hydroxybenzyl) glycine (H(2)glysal) with VOSO(4) gives [(glysal)VO(H(2)O)] (2) and reaction of salicylamide (Hsalam) with VOSO(4) in methanol gives [(salam)(2)VO] (3). The crystal structure of the oxido-bridged complex 1 is reported. The insulin-mimetic activity of all three complexes was evaluated with respect to their ability to phosphorylate protein kinase B (PKB). The speciations of complexes 1 and 2 were studied over the pH range 2-10. Complex 1 shows greater stability over the whole pH range but only 2 and 3 exhibit an insulin-mimetic effect.

Journal of Inorganic Biochemistry, 2009

The proligands PicMe-AaR (PicMe = methoxipicolyl-5-amide, where the amide substituent is an amino... more The proligands PicMe-AaR (PicMe = methoxipicolyl-5-amide, where the amide substituent is an amino acid AaR = HisH, HisMe, IleH, IleMe, TrpH, TrpMe, HTyrEt, tBuTyrMe, HThrMe, tBuThrMe) and the complexes [VO(Pic-AaR) 2 ] have been synthesised and characterised. A detailed EPR study of the VO 2+ / Pic-His systems in water revealed the predominance of the complex [VO(Pic-His)H 2 O] in the pH range 2-6, with tridentate coordination of Pic-His via the picolinate moiety and imidazole-Nd. Speciation analyses of the binary systems VO 2+ /Pic-Aa (Aa = His, Ile, Trp) and the ternary systems VO 2+ /Pic-Aa/B (Aa = His, Ile; B = citrate (cit), lactate (lac), phosphate) showed a predominance of the ternary complexes [VO(Pic-Aa)(cit/lac)] and [VO(Pic-Aa)(cit/lac)OH] À in the physiological pH regime. If, in addition, human serum albumin (HAS) and apotransferrin (Tf) are present, with all of the low and high molecular mass constituents in their blood serum concentrations, about two thirds of VO 2+ is bound to the protein, while there is still a sizable amount of ternary complex [VO(Pic-Aa)(cit/lac)] present (about 1/4 for Pic-His and 1/3 for Pic-Ile) when the vanadium(IV) concentration is relatively high; at lower concentrations Tf is the predominant binder. Insulin-mimetic studies for VO 2+ /Pic-Aa (Aa = His, Ile, Tyr and Trp), based on a lipolysis assay with rat adipocytes, provided IC 50 values of 0.41(1) for VO 2+ /Pic-His and VO 2+ /Pic-Ile, which compares with 0.87(17) for VOSO 4 .

Inorganic chemistry, Jan 18, 2018

British anti-Lewisite (2,3-dimerkaptopropan-1-ol, dimercaprol, BAL) is one of the best-known chel... more British anti-Lewisite (2,3-dimerkaptopropan-1-ol, dimercaprol, BAL) is one of the best-known chelator-type therapeutic agents against toxic metal ions and metalloids, especially arsenicals. Surprisingly, the mechanisms of action at the molecular level, as well as the coordination features of this traditional drug toward various arsenicals, are still poorly revealed. The present study on the interaction of arsenous acid (HAsO) with BAL, involving UV and NMR titrations, electrospray ionization mass spectrometry, and 2D NMR experiments combined with MP2 calculations, demonstrates that the reaction of HAsO with BAL at pH = 7.0 results in a more complex speciation than was assumed before. The three reactive hydroxyl groups of HAsO allow for interaction with three thiol moieties via condensation reaction, leading to the observed AsBAL and AsBAL complexes besides the AsBAL species. This indicates the strong propensity of inorganic As(III) to saturate its coordination sphere with thiolate g...

Current medicinal chemistry, Jan 6, 2018

Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal act... more Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids.

Inorganica Chimica Acta, 2017

The stoichiometry and thermodynamic stability of vanadium IV/V and copper II complexes of pyridox... more The stoichiometry and thermodynamic stability of vanadium IV/V and copper II complexes of pyridoxal thiosemicarbazone and pyridoxal-N 3 ,N 3-dimethylthiosemicarbazone have been determined by pH-potentiometry (V IV O), EPR (V IV O/Cu II), UV-Vis (Cu II , V IV O and V V) and 51 V-NMR spectroscopy (V V) in 30% (w/w) dimethyl sulfoxide/water solvent mixture. In all cases, mono-ligand complexes are formed in different protonation states. In addition, the proton-dissociation constants of the ligands were also determined by pH-potentiometry, UV-Vis and 1 H-NMR spectroscopy. The solid state structures of the monoprotonated forms (V V O 2 (L 1 H)×0.8H 2 O and V V O 2 (L 2 H)×0.8H 2 O) of the V V complexes were characterized by single-crystal X-ray diffraction analysis. The mono-ligand complexes of Cu II and V V are dominant at physiological pH. With all investigated metal ions the pyridoxal moiety of the ligand causes an extra deprotonation step between pH 4 and 7 due to the non-coordinating pyridine-NH +. The pyridoxal-containing ligands form somewhat more stable complexes with both V IV O and Cu II ions than the reference compound salicylaldehyde thiosemicarbazone. Dimethylation of the terminal amino group resulted in the formation of V V and Cu II complexes with even higher stability.

Coordination Chemistry Reviews, 2017

The paper deals with the so far most efficient antidiabetic transition metal compound family. It ... more The paper deals with the so far most efficient antidiabetic transition metal compound family. It focuses on the species distribution of the most frequently studied vanadium(IV,V) compounds in biology: in the gastro-intestinal tract (being important in absorption of the compounds), the blood serum (very likely the main route of their transport), the whole blood (recently the role of the red blood cells are also assumed in their transport) and in the cells (where glutathione and ATP may be the most important redox and complex formation partners of the original vanadium-"insulinomimetics"). The discussed details fit into the general view, but far from a complete and clear understanding of the pharmacodynamics of these antidiabetics. A lot more in vitro and mostly in vivo studies are necessary to justify their real clinical use. Contents 2.4. Speciation of vanadium with high molecular mass (HMM) constituents of blood serum 2.5 Speciation of vanadium(IV) and vanadium(V) in blood serum 2.6. Interactions of vanadium in the whole blood 2.7. Speciation of vanadium in the cells 3. Conclusions Acknowledgements References Abbreviations: GI, gastrointestinal; LMM, low molecular mass; HMM, high molecular mass; HIV, human immunodeficiency virus; DM, diabetes mellitus; STZ, streptozotocin; BMOV, bis(maltolato)oxovanadium(IV); BEOV, bis(ethylmaltolato)oxovanadium(IV); acac, acetylacetone; mal, maltol (3-hydroxy-2-methyl-4-pyrone); imal, isomaltol [1-(3-hydroxy-2furanyl) ethanone]; amal, allomaltol (3-hydroxy-6-methyl-4-pyrone); emal, ethyl maltol (3hydroxy-2-ethyl-4-pyrone); ipmal, isopropyl maltol (3-hydroxy-2-isopropyl-4-pyrone); alx, allixin (3-hydroxy-5-methoxy-6-methyl-2-pentyl-4-pyrone); koj, kojic acid [5-Hydroxy-2-(hydroxymethyl)-4-pyrone]; cur, curcumin; hpno, 2-hydroxypyridine N-oxide; dhp, 3hydroxy-1,2-dimethyl-4(1H)-pyridone; hopy, 1-hydroxy-2(1H)-pyrimidone; dmhopy, 1hydroxy-4,6-dimethyl-2(1H)-pyrimidone; mhopy, 1-hydroxy-6-methyl-2(1H)-pyrimidone; pic, picolinic acid; 6mpic, 6-methylpicolinic acid; 6etpic, 6-ethylpicolinic acid; 5ipic, 5iodopicolinic acid; 3mpic, 3-methylpicolinic acid; 3hpic, 3-hydroxypicolinic acid; dipic, 2,6dipicolinic acid; biguad, biguanide; metf, metformin (N',N'-dimethylbiguanide); mpno, 2mercaptopyridine N-oxide; ROS, reactive oxygen species; XANES, X-ray absorption near edge structure; Tf, transferrin(human); apoTf, apotransferrin(human); HSA, human serum transferrin; his, histidine; asp, aspartic acid; tyr, tyrosine; gly, glycine; NTS, N-terminal (binding) site; ATCUN, amino terminal Cu(II)-and Ni(II)-binding; MBS, multiple binding sites; IgG, immunoglobulin G; EPR, electron paramagnetic resonance; CD, circular dichroism; ICP-MS, inductively coupled plasma mass spectrometry; LC50, lethal concentration 50%; Hb, hemoglobin; RBC, red blood cell; GSH, glutathione; GSSG,

Journal of inorganic biochemistry, Mar 14, 2016

Two recently published Ru(III) complexes bearing (N2O2) tetradentate bis(aminophenolate) ligands,... more Two recently published Ru(III) complexes bearing (N2O2) tetradentate bis(aminophenolate) ligands, formulated as [Ru(III)(salan)(PPh3)Cl] (salan is the tetradentate ligand 6,6'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol) in complex 1, or 2,2'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol) in complex 2; PPh3 is triphenylphosphane) and found very active against ovarian and breast adenocarcinoma human cells were studied to outline their antitumor mode of action. The human cisplatin-sensitive ovarian adenocarcinoma line A2780 was used herein as the cell model. At a 24h challenge (similarly as found before for 72h) both complexes are active, their cytotoxicity being comparable to that of cisplatin in the same conditions. As a possible target in the cell for their action, the interaction of 1 and 2 with DNA was assessed through displacement of well-established DNA fluorescent probes (ethidium bromide, EB, and 4',6-d...

A támogatott kutatási projekt céljai (a) Réz-, kobalt-és vasionok aminosav komplexeinek (L-hiszti... more A támogatott kutatási projekt céljai (a) Réz-, kobalt-és vasionok aminosav komplexeinek (L-hisztidin, L-tirozin-és Lcisztein) elkészítése és rögzítése különféle hordozókon többféle módszerrel. (b) A katalizátorok jellemzése, és aktivitásuk/szelektivitásuk tesztelése egyszerű oxidációs/dizmutációs és összetettebb szerves kémiai oxidációs reakciókban. (c) A katalizátorok és a reakciók modellezése kvantumkémiai módszerekkel. A kutatások menete és az elért eredmények A kutatás kezdő évében (2006) különféle réz-tirozin és réz-hisztidin komplexek kovalens immobilizálására került sor. A szintézisek kézbentartásának érdekében C-illetve N-terminálison védett aminosavakkal dolgoztunk. Hordozóként használtunk klórpropilezett szilikagélt és klórozott polisztirolt egyaránt. Szilikagél használatakor a komplexek kialakítására a védőcsoport eltávolítása után került sor, azaz a heterogenizált komplex ligandumjai (tirozin vagy hisztidin) védőcsoport nélküli aminosavak voltak. A gyanta használatakor a rézkomplex kialakítása a védett ligandumokkal történt. A kapott heterogenizált komplexeket infravörös spektroszkópiával jellemeztük. Egyéb analitikai módszerekkel (atomabszorpciós spektroszkópia, Kjeldahl-módszer) meghatároztuk a koordinációs számot, és a feltételezett szerkezeteket modelleztük is (MM+ kód). A szilikagélen kialakított komplexek kataláz-aktivitását teszteltük, és, meglepetésünkre, tirozináz-aktivitást is találtunk, amikor a ligandum a tirozin volt. Kapott eredményeinket két közleményben foglaltuk össze [Jakab, I.N., Szabó, É., Hernadi, K., Pálinkó, I.: The synthesis and the catalytic (catalase and tyrosinase) activities of amino acid copper complexes covalently grafted onto silica gel, Sampling

Polyhedron, 2014

The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4hydr... more The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4hydroxy-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 dissoci ation constants o f 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 o f Cu(II) in human embryonic kidney HEK-293 cells. Our studies revealed, how ever, that none of the chelators were efficient enough to withdraw these metal ions from the amyloid aggregates.

Journal of Pharmaceutical and Biomedical Analysis, 2011

The lipophilic character of several carrier ligands of antidiabetic Zn(II) and VO(IV) metal compl... more The lipophilic character of several carrier ligands of antidiabetic Zn(II) and VO(IV) metal complexes were characterized by the traditional saturation shake flask method based on n-octanol/water partitioning. The transfer of the neutral ligand species to the organic phase was followed by UV spectrophotometry at various pH and the partition and distribution coefficients were calculated with the help of the proton dissociation constants and the spectra of the individual ligand species. Partition and distribution coefficients of the Zn(II) and VO(IV) complexes were determined by analysis of the metal ion content of the aqueous phases before and after separation by ICP-AES, their UV spectra and the corresponding concentration distribution curves. Results revealed the fairly hydrophilic character both the carrier ligands and their neutral Zn(II) and VO(IV) complexes. A quasi-linear relationship was found between logP of the ligands and that of the metal species in the case of the ligands studied with the exception of the picolinates. Importance of the knowledge of the chemical speciation (i.e. stoichiometry and stability constants) was also highlighted for the characterization of the lipophilic character of the kinetically labile metal complexes.

Journal of Inorganic Biochemistry, 2013

Stoichiometry and stability of antitumor ruthenium(II)−η 6-p-cymene complexes of bidentate (O,O) ... more Stoichiometry and stability of antitumor ruthenium(II)−η 6-p-cymene complexes of bidentate (O,O) hydroxypyrone and (O,S) hydroxythiopyr(id)one type ligands were determined by pHpotentiometry, 1 H NMR spectroscopy and UV−Vis spectrophotometry in aqueous solution and in dependence of chloride ion concentration. Formation of mono-ligand complexes with moderate stability was found in the case of the hydroxypyrone ligands (ethyl maltol and allomaltol) predominating at the physiological pH range. These complexes decompose to the dinuclear tri-hydroxido bridged species [{Ru II (η 6-p-cymene} 2 (OH) 3 ] and to the metal-free ligand at basic pH values. In addition, formation of a hydroxido [Ru II (η 6-p-cymene)(L)(OH)] species was found. The hydroxythiopyr(id)one ligands (thiomaltol, thioallomaltol, 3-hydroxy-1,2-dimethyl-thiopyridone) form complexes of significantly higher stability compared with the hydroxypyrones; their complexes are biologically more active, the simultaneous bi-and monodentate coordination of the ligands in the bis complexes (ML 2 and ML 2 H) was also demonstrated. In the case of thiomaltol, formation of tris complexes is also likely at high pH. The replacement of the chlorido by the aqua ligand in the [Ru II (η 6-p-cymene)(L)(Cl)] species was monitored, which is an important activation step in the course of the mode of action of the complexes, facilitating binding to biological targets.

Dalton Transactions, 2009

The interactions of various insulin mimetic oxovanadium(IV) compounds with serum proteins were st... more The interactions of various insulin mimetic oxovanadium(IV) compounds with serum proteins were studied in model systems and in ex vivo samples. For the modeling study, an earlier in situ method was extended and applied to the formation of ternary complexes of apotransferrin (apoTf)-V(IV)O-maltol (mal) and 1,2-dimethyl-3-hydroxy-4(1H)-pyridinone (dhp). Both systems were evaluated via simultaneous CD and EPR measurements. Determination of the formation constants of the ternary complexes allowed the calculation of more accurate stability constants for the V(IV)O-apoTf parent complexes and establishment of a better model for drug speciation in serum. It was found that dhp and the synergistic carbonate are non-competitive binders. Based on the stability constants obtained for V(IV)O-apoTf complexes and estimated for V(IV)O-HSA (= human serum albumin), modeling calculations were performed on the distribution of V(IV)O among the components of blood serum. The results were confirmed by HPLC-ICP-MS (liquid chromatography-inductively coupled plasma spectroscopy-mass spectrometry) measurements. The ex vivo interactions of the V(IV)O complexes formed with mal, picolinic acid (pic) and dhp with serum protein standards and also with human serum samples were evaluated. The proteins were firstly separated by (HPLC), and the V content of each fraction was determined by ICP-MS. All the studied V(IV)O compounds displayed similar chromatographic profiles, associated almost exclusively with apotransferrin as predicted by the modeling calculations. Under physiological conditions, the interactions with HSA of all of the species under study were negligible. Therefore Tf seems to be the main V(IV)O transporter in the serum under in vitro conditions, and this association is practically independent of the chemical form in which V(IV)O is administered.

Dalton Trans., 2012

Figure S1. Molar absorption spectra of the Cu(II) complexes formed with (GH) 2 K (a) and (HH) 2 K... more Figure S1. Molar absorption spectra of the Cu(II) complexes formed with (GH) 2 K (a) and (HH) 2 K (b).

Chemistry - A European Journal, 2004

The Schiff base N,N'-ethylenebis(pyridoxylideneiminato) (H 2 pyr 2 en, 1) was synthesized by reac... more The Schiff base N,N'-ethylenebis(pyridoxylideneiminato) (H 2 pyr 2 en, 1) was synthesized by reaction of pyridoxal with ethylenediamine; reduction of H 2 pyr 2 en with NaBH 4 yielded the reduced Schiff base N,N'-ethylenebis-(pyridoxylaminato) (H 2 Rpyr 2 en, 2); their crystal structures were determined by X-ray diffraction. The totally protonated forms of 1 and 2 correspond to H 6 L 4 + , and all protonation constants were determined by pH-potentiometric and 1 H NMR titrations. Several vanadium(iv) and vanadium(v) complexes of these and other related ligands were prepared and characterized in solution and in the solid state. The X-ray crystal structure of [V V O 2 (HRpyr 2 en)] shows the metal in a distorted octahedral geometry, with the ligand coordinated through the N-amine and O-phenolato moieties, with one of the pyridine-N atoms protonated. Crystals of [(V V O 2) 2 (pyren) 2 ]¥2 H 2 O were obtained from solutions containing H 2 pyr 2 en and oxovanadium(iv), where Hpyren is the ™half∫ Schiff base of pyridoxal and ethylenediamine. The complexation of V IV O 2 + and V V O 2 + with H 2 pyr 2 en, H 2 Rpyr 2 en and pyridoxamine in aqueous solution were studied by pH-potentiometry, UV/Vis absorption spectrophotometry, as well as by EPR spectroscopy for the V IV O systems and 1 H and 51 V NMR spectroscopy for the V V O 2 systems. Very significant differences in the metal-binding abilities of the ligands were found. Both 1 and 2 act as tetradentate ligands. H 2 Rpyr 2 en is stable to hydrolysis and several isomers form in solution, namely cis±trans type complexes with V IV O, and a-cis-and b-cis-type complexes with V V O 2. The pyridinium-N atoms of the pyridoxal rings do not take part in the coordination but are involved in acid±base reactions that affect the number, type, and relative amount of the isomers of the V IV O± H 2 Rpyr 2 en and V V O 2 ±H 2 Rpyr 2 en complexes present in solution. DFT calculations were carried out and support the formation and identification of the isomers detected by EPR or NMR spectroscopy, and the strong equatorial and axial binding of the O-phenolato in V IV O and V V O 2 complexes. Moreover, the DFT calculations done for the [V IV O(H 2 Rpyr 2 en)] system indicate that for almost all complexes the presence of a sixth equatorial or axial H 2 O ligand leads to much more stable compounds.

Open Chemistry, 2006

An imidazolate-bridged copper(II)-zinc(II) complex (Cu(II)-diethylenetriamino-μ-imidazolato-Zn(II... more An imidazolate-bridged copper(II)-zinc(II) complex (Cu(II)-diethylenetriamino-μ-imidazolato-Zn(II)-tris(2-aminoethyl)amine perchlorate (denoted as “Cu,Zn complex”) and a simple copper(II) complex (Cu(II)-tris(2-aminoethyl) amine chloride (“Cu-tren”) were prepared and immobilised on silica gel (by hydrogen or covalent bonds) and montmorillonite (by ion exchange). The immobilised substances were characterised by FT-IR spectroscopy and their thermal characteristics were also studied. The obtained materials were tested in two probe reactions: catalytic oxidation of 3,5-di-tert-butyl catechol (DTBC) (catecholase activity) and the decomposition of hydrogen peroxide (catalase activity). It was found that the catecholase activity of the Cu,Zn complex increased considerably upon immobilization on silica gel via hydrogen bonds and intercalation by ion exchange among the layers of montmorillonite. The imidazolate-bridged copper(II)-zinc(II) complex and its immobilised versions were inactive in...

Bioorganic & Medicinal Chemistry, 2011

The specific binding of carrier ligands of antidiabetic vanadium(IV) and zinc(II) complexes into ... more The specific binding of carrier ligands of antidiabetic vanadium(IV) and zinc(II) complexes into drug binding pockets of human serum albumin (HSA) has been investigated via displacement reactions of site markers such as warfarin and dansylglycine by different spectroscopic (fluorescence, circular dichroism, NMR) and separation methods (capillary zone electrophoresis, ultrafiltration-UV). Conditional stability constants of the ligands were calculated for the binding at sites I and II of HSA. Binding site I was found to be the primary binding site for 2,6-pyridine dicarboxylic acid (dipic) and picolinic acid (pic), and site II for 6-methylpicolinic acid (6-Mepic) and maltol, although dipic, 6-Mepic and pic displace both site markers at differing extents. The experimental data is complemented by protein-ligand docking calculations for dipic and 6-Mepic which support the observations.

Biochemical and Biophysical Research Communications, 2006

Previously, we reported that intraperitoneal injections of the Zn(II) complex (Zn(alx) 2) with al... more Previously, we reported that intraperitoneal injections of the Zn(II) complex (Zn(alx) 2) with allixin, which is isolated from dry garlic, with a Zn(O 4) coordination environment, exhibited high anti-diabetic effects in obesity-linked type 2 diabetic KKA y mice. However, this complex exhibited low activity when administered orally. To improve the effect of Zn(alx) 2 , we prepared a novel Zn(II) complex with the allixin-derivative bis(1,6-dimethyl-3-hydroxy-5-methoxy-2-pentyl-1,4-dihydropyridine-4-thionato)Zn(II), abbreviated as Zn(II)-thioallixin-N-methyl (Zn(tanm) 2), having a Zn(S 2 O 2) coordination environment; this complex has extremely high in vitro insulin-like activity. Because Zn was extensively absorbed from the gastrointestinal tract when Zn(tanm) 2 was orally administered, its anti-diabetic effects were examined in KKA y mice. Daily oral administrations of Zn(tanm) 2 for 4 weeks in KKA y mice significantly improved hyperglycemia, glucose intolerance, insulin resistance, hyperleptinemia, obesity, and hypertension. Interestingly, Zn(tanm) 2 increased depressed plasma adiponectin levels in the mice. Here, we propose that Zn(tanm) 2 will be an orally active therapeutic for obesity-linked type 2 diabetes and metabolic syndromes.

Coordination Chemistry Reviews, 2017

This review provides definitions and examples of chemical speciation, as well as giving details o... more This review provides definitions and examples of chemical speciation, as well as giving details of the differences in speciation between labile and inert systems. By moving from the simple to the complex, starting with simple species distribution calculation methods based on solution structural studies, this review progresses to modeling calculations that are applicable to "real-world" systems. The biological and or medicinal speciation of the following metal ions are discussed (modeling and experimental confirmation of the calculation results as well as kinetic aspects of their changes in speciation): Al(III), Fe(III), Ga(III), Gd(III), Ru(III), Ca(II), Cu(II), Pd(II), V(IV)O, V(V), and Zn(II)). Brief introductions are also given to trace analytical and environmental speciation. The current status and future possibilities of speciation studies (evaluation and prediction of speciation data), data collection, and databases are also critically discussed.

Journal of Organometallic Chemistry, 2013

Ru II ( 6-p-cymene) complexes of two bidentate (O,O) alkoxycarbonylmethyl-3-hydroxy-2(1H)-pyrido... more Ru II ( 6-p-cymene) complexes of two bidentate (O,O) alkoxycarbonylmethyl-3-hydroxy-2(1H)-pyridone ligands exhibit in vitro antitumor activity. We determined their stoichiometry and stability in aqueous solution by pH-potentiometry, 1 H NMR spectroscopy and UV-Vis spectrophotometry and also characterized the proton dissociation processes of the ligands. Formation of mono-ligand complexes with moderate stability was found to predominate in the physiological pH range. Moreover, the chlorido/aqua co-ligand exchange processes of the [Ru II ( 6-p-cymene)(L)(H 2 O)] + species were also monitored and 55-65% of the aqua ligand was found to be replaced by chloride in 0.2 M KCl containing aqueous solutions. Under basic conditions, the complexes decompose to dinuclear tri-hydroxido-bridged [Ru  ( 6-pcymene) 2 (OH) 3 ] + and metal-free ligand and also a hydroxido species [Ru II ( 6-pcymene)(L)(OH)] was found. Furthermore, the ligands contain an ester functional group, which may hydrolyze at basic pH, which is however negligible at acidic or neutral pH.

Journal of Inorganic Biochemistry, 2011

Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the ... more Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the oxidovanadium(V) oxido-bridged dimer [{(papy)(VO)}(2) μ-O)] (1). Similarly, reaction of N-(2-hydroxybenzyl) glycine (H(2)glysal) with VOSO(4) gives [(glysal)VO(H(2)O)] (2) and reaction of salicylamide (Hsalam) with VOSO(4) in methanol gives [(salam)(2)VO] (3). The crystal structure of the oxido-bridged complex 1 is reported. The insulin-mimetic activity of all three complexes was evaluated with respect to their ability to phosphorylate protein kinase B (PKB). The speciations of complexes 1 and 2 were studied over the pH range 2-10. Complex 1 shows greater stability over the whole pH range but only 2 and 3 exhibit an insulin-mimetic effect.

Journal of Inorganic Biochemistry, 2009

The proligands PicMe-AaR (PicMe = methoxipicolyl-5-amide, where the amide substituent is an amino... more The proligands PicMe-AaR (PicMe = methoxipicolyl-5-amide, where the amide substituent is an amino acid AaR = HisH, HisMe, IleH, IleMe, TrpH, TrpMe, HTyrEt, tBuTyrMe, HThrMe, tBuThrMe) and the complexes [VO(Pic-AaR) 2 ] have been synthesised and characterised. A detailed EPR study of the VO 2+ / Pic-His systems in water revealed the predominance of the complex [VO(Pic-His)H 2 O] in the pH range 2-6, with tridentate coordination of Pic-His via the picolinate moiety and imidazole-Nd. Speciation analyses of the binary systems VO 2+ /Pic-Aa (Aa = His, Ile, Trp) and the ternary systems VO 2+ /Pic-Aa/B (Aa = His, Ile; B = citrate (cit), lactate (lac), phosphate) showed a predominance of the ternary complexes [VO(Pic-Aa)(cit/lac)] and [VO(Pic-Aa)(cit/lac)OH] À in the physiological pH regime. If, in addition, human serum albumin (HAS) and apotransferrin (Tf) are present, with all of the low and high molecular mass constituents in their blood serum concentrations, about two thirds of VO 2+ is bound to the protein, while there is still a sizable amount of ternary complex [VO(Pic-Aa)(cit/lac)] present (about 1/4 for Pic-His and 1/3 for Pic-Ile) when the vanadium(IV) concentration is relatively high; at lower concentrations Tf is the predominant binder. Insulin-mimetic studies for VO 2+ /Pic-Aa (Aa = His, Ile, Tyr and Trp), based on a lipolysis assay with rat adipocytes, provided IC 50 values of 0.41(1) for VO 2+ /Pic-His and VO 2+ /Pic-Ile, which compares with 0.87(17) for VOSO 4 .