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Vanadium compounds mimic insulin actions in different cell types. The present study concerns the insulin-like effects of three vanadium(V) derivatives and one vanadium(IV) complex on osteoblast-like (UMR106 and MC3T3E1) cells in culture. The vanadium oxalate and vanadium citrate complexes hydrolyzed completely under the culture conditions, whereas more than 40% of the vanadium tartrate and nitrilotriacetate complexes remained. Vanadate, as well as vanadium oxalate, citrate, and tartrate complexes enhanced cell proliferation (as measured by the crystal violet assay), glucose consumption, and protein content in UMR106 and MC3T3E1 osteoblast- like cells. The vanadium nitrilotriacetate complex (the only peroxo complex tested) stimulated cell proliferation in UMR106 but not in MC3T3E1 cells. This derivative strongly transformed the morphology of the MC3T3E1 cells. All vanadium(V) compounds inhibited cell differentiation (alkaline phosphatase activity) in UMR106 cells. Our data are consistent with the interpretation that vanadium oxalate and citrate complexes hydrolyze to vanadate. Vanadium nitrilotriacetate would appear to be toxic for normal MC3T3E1 osteoblasts. In contrast, the vanadium tartrate complex induced a proliferative effect however, it did not alter cell differentiation. 338 1 7 14 Cited By :61

The stability of 11 vanadium compounds is tested under physiological conditions and in administration fluids. Several compounds including those currently used as insulin-mimetic agents in animal and human studies are stable upon dissolution in distilled water but lack such stability in distilled water at pH7. Complex lability may result in decomposition at neutral pH and thus may compromise the effectiveness of these compounds as therapeutic agents Even well characterized vanadium compounds are surprisingly labile. Sufficiently stable complexes such as the VEDTA complex will only slowly reduce, however, none of the vanadium compounds currently used as insulin-mimetic agents show the high stability of the VEDTA complex. Both the bis(maltolato)oxovanadium(IV) and peroxovanadium complexes extend the insulin-mimetic action of vanadate in reducing cellular environments probably by increased lifetimes under physiological conditions and/or by decomposing to other insulin mimetic compounds. For example, treatment with two equivalents of glutathione or other thiols the (dipicolinato)peroxovanadate(V) forms 9dipicolinato)oxovanadate(V) and vanadate, which are both insulin-mimetic vanadium(V) compounds and can continue to act. The reactivity of vanadate under physiological conditions effects a multitude of biological responses. Other vanadium complexes may mimic insulin but not induce similar responses if the vanadate formation is blocked or reduced. We conclude that three properties, stability, lability and redox chemistry are critical to prolong the half-life of the insulin-mimetic form of vanadium compounds under physiological conditions and should all be considered in development of vanadium-based oral insulin-mimetic agents. © 1995 Kluwer Academic Publishers. 153 1-2 17 24 Cited By :81

Although dogma states that vanadate is readily reduced by glutathione, cysteine, and other thiols, there are several examples documenting that vanadium(V)-sulfur complexes can form and be observed. This conundrum has impacted life scientists for more than two decades. Investigation of this problem requires an understanding of both the complexes that form from vanadium(IV) and (V) and a representative thiol in aqueous solution. The reactions of vanadate and hydrated vanadyl cation with 2-mercaptoethanol have been investigated using multinuclear NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopy. Vanadate forms a stable complex of 2:2 stoichiometry with 2-mercaptoethanol at neutral and alkaline pH. In contrast, vanadate can oxidize 2-mercaptoethanol this process is favored at low pH and high solute concentrations. The complex that forms between aqueous vanadium(IV) and 2-mercaptoethanol has a 1:2 stoichiometry and can be observed at high pH and high 2-mercaptoethanol concentration. The solution structures have been deduced based on coordination induced chemical shifts and speciation diagrams prepared. This work demonstrates that both vanadium(IV) and (V)-thiol complexes form and that redox chemistry also takes place. Whether reduction of vanadate takes place is governed by a combination of parameters: pH, solute- and vanadate-concentrations and the presence of other complexing ligands. On the basis of these results it is now possible to understand the distribution of vanadium in oxidation states (IV) and (V) in the presence of glutathione, cysteine, and other thiols and begin to evaluate the forms of the vanadium compounds that exert a particular biological effect including the insulin-enhancing agents, antiamoebic agents, and interactions with vanadium binding proteins. © 2010 American Chemical Society. 49 9 4245 4256 Cited By :59

The full speciation has been determined in the aqueous vanadate-uridine (UrH2) and vanadate-uridine-imidazole (ImH) systems. The studies performed allow direct comparison with the corresponding adenosine systems, and the role of the pyrimidine and purine bases on various complex properties could be evaluated. The studies also provide insight into possible biological mechanism of action. Formation constants have been determined in 0.600 M Na(Cl) medium at 25 °C in the pH range 2-11, using a combination of potentiometry and 51V NMR spectroscopy. In the H+-H2VO4---UrH2 system, two dimeric complexes form: V2Ur2 2- with log β= 7.66 ± 0.02 and V2Ur2 3- with log β= 1.09 ± 0.04. The errors given are 3ω. Both species give rise to NMR resonances at -523 ppm. A minor 51V NMR resonance at -507 ppm is probably originating from a VUr2- species. No evidence was found for a 1:1 species at -523 ppm or a 1:1 species with 51V NMR shift superimposed on the vanadate monomer. In the H+-H2VO4 - UrH2-ImH system, two monomeric, mixed ligand species are formed: VUrIm- with log β= 3.12 ± 0.04 and VUrIm2- with log β= -6.26 ± 0.20. The pKa values for the V2Ur2 2- and VUrIm- species, 8.75 and 9.38, are both close to that of uridine (9.02) and are consistent with the interpretation that the deprotonation site is located on the base pan of the nucleoside. For both the V2Ur2 2- and VUrImn- species, isomers have been identified. Equilibrium conditions are illustrated in distribution diagrams. A quantitative comparison with the analogous vanadate-adenosine and vanadate-adenosine-imidazole systems is presented. Furthermore, the solution structure of V2Ur2 2- was examined using 17O NMR spectroscopy. The complex gives rise to a broad resonance at approximately -1010 ppm, which at higher temperature sharpened into two signals of equal intensities at -1007 and -1032 ppm. This spectrum is consistent only with a solution structure containing pentacoordinate vanadium in an arrangement in which one hydroxyl group of the uridine forms an ester with one vanadium atom, and the other hydroxyl group bridges the two vanadium atoms. In addition, 13C NMR studies revealed that the dinuclear vanadate-uridine species exchange while no evidence for intermolecular exchange between the complexes and free uridine was observed. The similarity between the vanadate-uridine and vanadate-adenosine complexes suggests that the role of the base in these complexes is very limited with respect to structural features and thermodynamic and kinetic properties. 37 24 6153 6160 Cited By :23

β= 102.53(2)° Z = 4. Crystal data for (NH4)[V2(O)2(μ-O)(Hhida) 2]·H2O (3): monoclinic β= 106.33(2)° A mononuclear vanadium(IV), a mononuclear vanadium(V), and a binuclear mixed valence vanadium(IV/V) complex with the ligand N-(2-hydroxyethyl)iminodiacetic acid (H3hida) have been structurally characterized. Crystal data for [VO(Hhida)(H2O)]·CH3OH (1): orthorhombic P212121 a = 6.940(2), b = 9.745(3), c = 18.539-(4) Å Z = 4. Crystal data for Na[V(O)2(Hhida)2]·4H2O (2): monoclinic P21/c a = 6.333(2), b = 18.796(2), c = 11.5040(10) Å C2/c a = 18.880(2), b = 7.395(2), c = 16.010(2) Å Z = 4. The mononuclear vanadium(IV) and vanadium(V) complexes are formed from the monoprotonated Hhida2- ligand, and their structural and magnetic characteristics are as expected for six-coordinate vanadium complexes. An interesting structural feature in these complexes is the fact that the two carboxylate moieties are coordinated trans to one another, whereas the carboxylate moieties are coordinated in a cis fashion in previously characterized complexes. The aqueous solution properties of the vanadium(IV) and -(V) complexes are consistent with their structures. The vanadium(V) complex was previously characterized in the current study structural characterization in the solid state is provided. X-ray crystallography and magnetic methods show that the mixed valence complex contains two indistinguishable vanadium atoms the thermal ellipsoid of the bridging oxygen atom suggests a type III complex in the solid state. Magnetic methods show that the mixed valence complex contains a free electron. Characterization of aqueous solutions of the mixed valence complex by UV/vis and EPR spectroscopies suggests that the complex may be described as a type II complex. The Hhida2- complexes have some similarities, but also some significant differences, with complexes of related ligands, such as nitrilotriacetate (nta), N-(2-pyridylmethyl)iminodiacetate (pmida), and N-(S)-[1-(2-pyridyl)ethyl]iminodiacetate (s-peida). Perhaps most importantly, the mixed valence Hhida2- complex is significantly less stable than the corresponding pmida and s-peida complexes of similar overall charge but very similar in stability to the nta and V2O33+ complexes with higher charges. Thus, there is the potential for designing stable mixed valence dimers. 36 8 1657 1668 Cited By :93

119 23 5447 5448 Cited By :104

A novel series of vanadium(V) hydroxylamido complexes with weak ligands including glycine, [VO-(NH2O)2(Glycine)]· H2O (1) serine, [VO(NH2O)2(Serine)]·H2O (2) glycylglycine, [VO(NH2O)2(GlyGly)]·H2O (3) and imidazole, [VO(NH2O)2(imidazole)2]Cl (4) were prepared and characterized both in solution and in the solid state. All complexes were prepared in aqueous solution at neutral pH at ambient temperature and as crystalline solids. The vanadium atom in these four complexes is seven-coordinate with pentagonal bipyramidal geometry. In complexes 1-3 the hydroxylamido groups are coordinated side-on with the hydroxylamido nitrogen cis to the organic ligand in the equatorial plane. In complex 4, the hydroxylamido groups are coordinated side-on with the hydroxylamido nitrogen trans to the imidazole ligand in the equatorial plane. The UV/vis spectra of these complexes were also examined, and the absorbance peaks show similarities between the properties of the vanadium(V) hydroxylamido complexes and known side-on peroxovanadium complexes. Multinuclear NMR studies were conducted to characterize the solution structure and properties of compounds 1-4. A particularly detailed study of compound 3 was carried out since the analogous vanadium(V) peroxo complex could also be prepared. Complex 4 was less labile and more stable than the corresponding diperoxovanadium(V)-imidazole complex, H[VO(O2)2(imidazole)] (5). In solution the inherent asymmetry of the hydroxylamido ligand has facilitated an in-depth study of ligand exchange. Upon dissolution, compound 4 forms three isomeric complexes, all of which have one of the original two-coordinated imidazole groups in the complex dissociated. 1D and 2D EXSY and multinuclear NMR spectroscopies were used to examine the stoichiometry of the isomers, their structures, and the dynamics of their ligand exchanges. Specifically, both inter- and intramolecular exchanges were observed for the dihydroxylamine-vanadium(V)-imidazole involving both the coordinated imidazole and the coordinated hydroxylamido groups. The intramolecular exchange of the coordinated imidazole in 5 was compared to the exchange in the hydroxylamido complex, and the hydroxylamido compounds were found to have some properties that may be advantageous over those of the diperoxovanadium(V) complexes. In summary, evidence was generated to support the existence of a novel and unprecedented asymmetric hydroxylamido-metal complex as well as the first isolation and characterization of a vanadium(V)-imidazole complex not enjoying stabilization by other organic ligands. 119 38 8901 8915 Cited By :91

Vanadium compounds mimic insulin actions in different cell types. The present study concerns the insulin-like effects of three vanadium(V) derivatives and one vanadium(IV) complex on osteoblast-like (UMR106 and MC3T3E1) cells in culture. The vanadium oxalate and vanadium citrate complexes hydrolyzed completely under the culture conditions, whereas more than 40% of the vanadium tartrate and nitrilotriacetate complexes remained. Vanadate, as well as vanadium oxalate, citrate, and tartrate complexes enhanced cell proliferation (as measured by the crystal violet assay), glucose consumption, and protein content in UMR106 and MC3T3E1 osteoblast-like cells. The vanadium nitrilotriacetate complex (the only peroxo complex tested) stimulated cell proliferation in UMR106 but not in MC3T3E1 cells. This derivative strongly transformed the morphology of the MC3T3E1 cells. All vanadium(V) compounds inhibited cell differentiation (alkaline phosphatase activity) in UMR106 cells. Our data are consistent with the interpretation that vanadium oxalate and citrate complexes hydrolyze to vanadate. Vanadium nitrilotriacetate would appear to be toxic for normal MC3T3E1 osteoblasts. In contrast, the vanadium tartrate complex induced a proliferative effect; however, it did not alter cell differentiation., Facultad de Ciencias Exactas

A new series of vanadium-(IV) and -(V) complexes with ligands containing functionalities including hydroxyethyl, carboxylate, amine, pyridyl and benzimidazole have been prepared. The crystal structures of three complexes have been determined. All the vanadium atoms are six-co-ordinate even though previous complexes of the diethanolamine type have contained five-co-ordinate vanadium. The V-N (amine) bonds of the benzimidazole complexes are significantly longer than those of pyridyl complexes. An empirical relationship between pKa value of the protonated ligand and the V-N (amine) bond length (trans to an oxo group) of the corresponding vanadium-(IV), -(V) and -(IV/V) complexes was observed. Spectroscopic studies (NMR, ESR and UV/VIS) showed that the complexes remain intact in aqueous solution. In general, the hydroxyethyl substituted vanadium complexes are less stable than corresponding acetate substituted ones and the benzimidazole complexes are less stable than corresponding pyridyl complexes. The combined knowledge concerning the properties of all these complexes provides an excellent platform to design new vanadium complexes pertinent to biological applications. 16 2799 2812 Cited By :36

Vanadium compounds, particularly in oxidation state V, are potent inhibitors of phosphoryl group transfer enzymes. In this paper the existance of a correlation between the coordination geometry of a series of vanadium dipicolinate complexes and their potency as inhibitors for chicken intestinal alkaline phosphatase is examined. We find that within a limited series of vanadium compounds the five-coordinate derivatives are the most potent inhibitors. 109 1-4 245 248 Cited By :32

The solution properties of two isomeric forms of the V-EDDA complex (the symmetric α-cis and asymmetric β-cis) have been studied using multinuclear NMR spectroscopy. The isomerization constant of the aqueous equilibrium mixture expressed as [α-cis]/[β-cis] increased on the addition of organic solvents (methanol, formamide, and DMSO) and decreased on the addition of salts (NaCl, NaClO4, and NH4Cl). The isomerization constant and corresponding thermodynamic parameters were determined under a variety of conditions. The solution studies were consistent with the interpretation that solvation is the major contributor to isomer stability. Solid state characterization of the β-cis isomer of NH4[VO2(EDDA)] confirmed this conclusion and allowed detailed examination of the role of hydrogen bonding in this complex. The structural parameters for this complex are triclinic, P1̄, a = 6.787(1) Å, b = 7.272(1) Å, c = 11.014(1) Å, α = 95.084(9)°, β= 92.805(8)°, and γ = 100.009(9)°. The dynamic processes of these complexes were examined in water and in water-DMSO mixtures resulting in observation of an unknown intramolecular dynamic process. The extent to which this complex responds to the environment is discussed, and its implications for biological studies and the mechanism of action of vanadium compounds are briefly considered. 35 12 3599 3606

The solution structure and rate of formation for a vanadium(V)-peptide complex, vanadium(V)-glycine-tyrosine (V-Gly-Tyr), is examined. Multinuclear NMR spectroscopic studies suggest the amide nitrogen is deprotonated and chelated to the vanadium as observed in peptide complexes of Ni(II) and Cu(II). The carboxylate and the amine groups in the dipeptide also appear to be chelated to the vanadium atom. The rate law for V-Gly-Tyr complex formation suggests that the complex is generated according to two major pathways, both involving H2VO4 − and deprotonated glycine-tyrosine dipeptide (Gly-Tyr−), one with and one without acid catalysis. The rate constant for the first pathway was 1.0 (±0.1) M−2 min‒1 (0.017 (±0.002) M‒2 s‒1), and the rate constant for the second pathway was 1.5 (±0.1) M‒1 min−1 (0.025 (±0.003) M−1 s‒1) The kinetics of complex formation were found to be significantly different from reported vanadate complexes such as vanadate dimer, vanadium(V)- alizarin, vanadium(V)-N-[tris(hydroxymethyl)methyl]glycine, vanadium(V)-EDTA, and vanadium(V)-ATPase. All of the previously studied complexes formed with H3O+ independent rate constants of about 104 M−1 s−1. The slow rates of formation of V-Gly-Tyr imply that equilibrium in such solutions is only slowly achieved. Time dependence curves reveal that the other complexes in the reaction between vanadate and Gly-Tyr form even more slowly however, such complexes are likely to be oxidation products since these complexes were not observed when oxygen was excluded from the solutions. Only low levels of vanadium(IV) complexes were observed in the absence or the presence of oxygen, despite significant concentrations of oxidation products. These observations are consistent with the recycling of the vanadium(IV) to vanadium(V) under the consumption of oxygen. Increasing temperatures also increase the V-Gly-Tyr concentration, however, since the vanadate monomer (V1) concentration increases, little variation in the formation constant is observed. The reaction of vanadate with Gly-Ser was also found to be significantly slower than the formation of vanadate esters and required incubation for more than an hour before equilibrium was achieved. It appears that complex formation between vanadate and ligands containing the peptide functionalities occurs slowly, analogous to formation of peptide complexes of Ni(II) and Cu(II). © 1995, American Chemical Society. All rights reserved. 34 10 2524 2534 Cited By :63