Aqueous chemistry of the vanadium(III) (V(III)) and the V(III)-dipicolinate systems and a comparison of the effect of three oxidation states of vanadium compounds on diabetic hyperglycemia in rats

The aqueous vanadium(III) (V(III)) speciation chemistry of two dipicolinate-type complexes and the insulin-enhancing effects of V-dipicolinate (V-dipic) complexes in three different oxidation states (V(III), V(IV), and V(V)) have been studied in a chronic animal model system. The characterization of the V(III) species was carried out at low ionic strength to reflect physiological conditions and required an evaluation of the hydrolysis of V(III) at 0.20 M KCl. The aqueous V(III)-dipic and V(III)-dipic-OH systems were characterized, and complexes were observed from pH 2 to 7 at 0.2 M KCl. The V(III)-dipic system forms stable 1:2 complexes, whereas the V(III)-dipic-OH system forms stable 1:1 complexes. A comparison of these complexes with the V-pic system demonstrates that a second ligand has lower affinity for the V(III), presumably reflecting bidentate coordination of the second dipic(2)(-) to the V(III). The thermodynamic stability of the [V(III)(dipic)(2)](-) complex was compared to the stability of the corresponding V(IV) and V(V) complexes, and surprisingly, the V(III) complexes were found to be more stable than anticipated. Oral administration of three V-dipicolinate compounds in different oxidation states {H[V(III)(dipic)(2)H(2)O].3H(2)O, [V(IV)Odipic(H(2)O)(2)].2H(2)O, and NH(4)[V(V)O(2)dipic]} and the positive control, VOSO(4), significantly lowered diabetic hyperglycemia in rats with streptozotocin-induced diabetes. The diabetic animals treated with the V(III)- or V(IV)-dipic complexes had blood glucose levels that were statistically different from those of the diabetic group. The animals treated with the V(V)-dipic complex had the lowest blood glucose levels of the treated diabetic animals, which were statistically different from those of the diabetic group at all time points. Among the diabetic animals, complexation to dipic increased the serum levels of V after the administration of the V(V) and V(IV) complexes but not after the administration of the V(III) complex when data are normalized to the ingested dose of V. Because V compounds differing only in oxidation state have different biological properties, it is implied that redox processes must be important factors for the biological action of V compounds. We observe that the V(V)-dipic complex is the most effective insulin-enhancing agent, in contrast to previous studies in which the V(IV)-maltol complex is the most effective. We conclude that the effectiveness of complexed V is both ligand and oxidation state dependent.     

Cobalt(II) and cobalt(III) dipicolinate complexes: solid state,solution, and in vivo insulin-like properties

The synthesis and characterization of Co(II) and Co(III) 2,6-pyridinedicarboxylate (dipic(2-)) complexes are reported. Solid-state X-ray characterizations were performed on [Co(H(2)dipic)(dipic)].3H(2)O and [Co(dipic)(mu-dipic)Co(H(2)O)(5)].2H(2)O. Two coordination modes not previously observed in dipicolinate transition metal complexes were observed in these complexes; one involves metal coordination to the short C-O (C=O) bond, and the other involves metal coordination to a protonated oxygen atom. Solution studies, including paramagnetic NMR and UV-vis spectroscopy, were done showing the high stability and low lability of the Co(III) complex, whereas the Co(II) complexes exhibited ligand exchange in the presence of excess ligand. The [Co(dipic)(2)](2-) complex has pH dependent lability and in this regard is most similar to the [VO(2)dipic](-) complex. The [Co(dipic)(2)](2-) was found to be effective in reducing the hyperlipidemia of diabetes using oral administration in drinking water in rats with STZ-induced diabetes. Oral administration of VOSO(4) was used as a positive control for metal efficacy against diabetes. In addition to providing a framework to evaluate structure-function relationships of various transition metal complexes in alleviating the symptoms of diabetes, this work describes novel aspects of structural and solution cobalt chemistry.     

Reduction of vanadium(V) by L-ascorbic acid at low and neutral pH: kinetic, mechanistic, and spectroscopic characterization

L-Ascorbic acid interacts with vanadium(V) over the pH range of 0.4-7.0 to form three different coordination complexes. Both inner- and outer-sphere electron-transfer pathways are proposed to form vanadium(IV) complexes with L-ascorbate or dehydroascorbate, respectively. Effects of the pH on the coordination of L-ascorbic acid to the vanadium(V) center were observed and are presumably related to the speciation of the vanadium(V) ion. Three vanadium(IV) complexes were observed using ambient-temperature electron paramagnetic resonance spectroscopy. Two of these complexes are proposed to be vanadium(IV) L-ascorbate complexes, and one is consistent with a vanadium(IV) dehydroascorbic acid complex proposed earlier. These reduction reactions will occur under physiological conditions and could be important to the reduction of vanadium(V)-containing coordination complexes used as insulin-enhancing agents for treatment of diabetes.     

4-amino- and 4-nitrodipicolinatovanadium(V) complexes and their hydroxylamido derivatives: synthesis, aqueous, and solid-state properties

A number of 4-substituted, dipicolinatodioxovanadium(V) complexes and their hydroxylamido derivatives were synthesized to characterize the solid state and solution properties of five- and seven-coordinate vanadium(V) complexes. The X-ray crystal structures of Na[VO2dipic-NH2].2H2O (2) and K[VO2dipic-NO2] (3) show the vanadium adopting a distorted, trigonal-bipyramidal coordination environment similar to the parent coordination complex, [VO2dipic]- (1), reported previously as the Cs+ salt. The observed differences in the chemical shifts of the complexes both in the 1H (ca. 0.7-1.4 ppm) and 51V (ca. 1-11 ppm) NMR spectra were consistent with the electron-donating or electron-withdrawing properties of the substituent groups, respectively. Stoichiometric addition of a series of hydroxylamine ligands (H2NOH, MeHNOH, Me2NOH, and Et2NOH) to complexes 1-3 led to the formation of seven-coordinate vanadium(V) complexes. The X-ray crystal structure of [VO(dipic)(Me2NO)(H2O)].0.5H2O (1c) was found to be similar to the previously characterized complexes [VO(dipic)(H2NO)(H2O)] (1a) and [VO(dipic)(OO-tBu)(H2O)]. While only slight differences in the 1H NMR spectra were observed upon addition of the hydroxylamido ligand, the signals in the 51V NMR spectra change by up to 100 ppm. The addition of the hydroxylamido ligand increased the complex stability of complexes 2 and 3. Evidence for a nonstoichiometric redox reaction was found for the monoalkyl hydroxylamine ligand. The reaction of an unsaturated five-coordinate species with a hydroxylamine to form a seven-coordinate vanadium complex will, in general, dramatically increase the amounts of the vanadium compound that remain intact at pH values near neutral.     

Study of the Ternary Complex Formation Between Vanadium(III), Dipicolinic Acid and Small Blood Serum Bioligands

Ternary complex formation reactions were studied between vanadium(III), dipicolinic acid and small molecular weight blood serum components: lactic, oxalic, citric and ortophosphoric acids. The electromotive force measurement permitted us to determine the chemical speciation of the complexes formed. In the vanadium(III)–dipicolinic acid–lactic acid system the complexes detected were: V(dipic)(lac), V(dipic)(lac)(OH)⁻ and V(dipic)(lac)(OH)₂^2-(\mathrm{OH})_{2}^{2-}. In the vanadium(III)–dipicolinic acid–oxalic acid system the observed complexes were: V(dipic)(ox)⁻, V(dipic)(ox)(Hox)²⁻ and V(dipic)(ox)₂^3-(\mathrm{ox})_{2}^{3-}. In the vanadium(III)–dipicolinic acid–citric acid system the complexes V(dipic)(Hcit)⁻, V(dipic)(cit)²⁻, V(dipic)(cit)(OH)³⁻, V(dipic)(cit)(OH)₂^4-(\mathrm{OH})_{2}^{4-} and V(dipic)(cit)(OH)₃^5-(\mathrm{OH})_{3}^{5-} were detected. Finally in the vanadium(III)–dipicolinic acid–phosphoric acid system the complexes V(dipic)(H₂PO₄) and V(dipic)(HPO₄)⁻ were observed. The UV-vis spectra allowed us to perform a qualitative characterization of the complexes formed in aqueous solution.     

Correlation of Insulin‐Enhancing Properties of Vanadium‐Dipicolinate Complexes in Model Membrane Systems: Phospholipid Langmuir Monolayers and AOT Reverse Micelles

We explore the interactions of V^III‐, V^IV‐, and V^V‐2,6‐pyridinedicarboxylic acid (dipic) complexes with model membrane systems and whether these interactions correlate with the blood‐glucose‐lowering effects of these compounds on STZ‐induced diabetic rats. Two model systems, dipalmitoylphosphatidylcholine (DPPC) Langmuir monolayers and AOT (sodium bis(2‐ethylhexyl)sulfosuccinate) reverse micelles present controlled environments for the systematic study of these vanadium complexes interacting with self‐assembled lipids. Results from the Langmuir monolayer studies show that vanadium complexes in all three oxidation states interact with the DPPC monolayer; the V^III–phospholipid interactions result in a slight decrease in DPPC molecular area, whereas V^IV and V^V–phospholipid interactions appear to increase the DPPC molecular area, an observation consistent with penetration into the interface of this complex. Investigations also examined the interactions of V^III‐ and V^IV‐dipic complexes with polar interfaces in AOT reverse micelles. Electron paramagnetic resonance spectroscopic studies of V^IV complexes in reverse micelles indicate that the neutral and smaller 1:1 V^IV‐dipic complex penetrates the interface, whereas the larger 1:2 V^IV complex does not. UV/Vis spectroscopy studies of the anionic V^III‐dipic complex show only minor interactions. These results are in contrast to behavior of the V^V‐dipic complex, [VO₂(dipic)]^?, which penetrates the AOT/isooctane reverse micellar interface. These model membrane studies indicate that V^III‐, V^IV‐, and V^V‐dipic complexes interact with and penetrate the lipid interfaces differently, an effect that agrees with the compounds’ efficacy at lowering elevated blood glucose levels in diabetic rats.     

New insights into the interactions of serum proteins with bis(maltolato)oxovanadium(IV): transport and biotransformation of insulin-enhancing vanadium pharmaceuticals

Significant new insights into the interactions of the potent insulin-enhancing compound bis(maltolato)oxovanadium(IV) (BMOV) with the serum proteins, apo-transferrin and albumin, are presented. Identical reaction products are observed by electron paramagnetic resonance (EPR) with either BMOV or vanadyl sulfate (VOSO4) in solutions of human serum apo-transferrin. Further detailed study rules out the presence of a ternary ligand-vanadyl-transferrin complex proposed previously. By contrast, differences in reaction products are observed for the interactions of BMOV and VOSO4 with human serum albumin (HSA), wherein adduct formation between albumin and BMOV is detected. In BMOV-albumin solutions, vanadyl ions are bound in a unique manner not observed in comparable solutions of VOSO4 and albumin. Presentation of chelated vanadyl ions precludes binding at the numerous nonspecific sites and produces a unique EPR spectrum which is assigned to a BMOV-HSA adduct. The adduct species cannot be produced, however, from a solution of VOSO4 and HSA titrated with maltol. Addition of maltol to a VOSO4-HSA solution instead results in formation of a different end product which has been assigned as a ternary complex, VO(ma)(HSA). Furthermore, analysis of solution equilibria using a model system of BMOV with 1-methylimidazole (formation constant log K1 = 4.5(1), by difference electronic absorption spectroscopy) lends support to an adduct binding mode (VO(ma)2-HSA) proposed herein for BMOV and HSA. This detailed report of an in vitro reactivity difference between VOSO4 and BMOV may have bearing on the form of active vanadium metabolites delivered to target tissues. Albumin binding of vanadium chelates is seen to have a potentially dramatic effect on pharmacokinetics, transport, and efficacy of these antidiabetic chelates.     

Speciation of the Ternary Complexes of Vanadium(III)–Dipicolinic Acid and the Amino Acids Cysteine,Histidine, Aspartic and Glutamic Acids in 3.0 mol⋅dm<Superscript>−3</Superscript> KCl at 25 °C

In this work we present results for the speciation of the ternary complexes formed in the aqueous vanadium(III)–dipicolinic acid and the amino acids cysteine (H₂cys), histidine (Hhis), aspartic acid (H₂asp) and glutamic acid (H₂glu) systems (25 °C; 3.0 mol⋅dm⁻³ KCl as ionic medium), determined by means of potentiometric measurements. The potentiometric data were analyzed with the least-squares program LETAGROP, taking into account the hydrolysis of vanadium(III), the acid-base reactions of the ligands, and the binary complexes formed. Under the experimental conditions (vanadium(III) concentration = 2–3 mmol⋅dm⁻³ and vanadium(III): dipicolinic acid: amino acid molar ratio 1:1:1, 1:1:2 and 1:2:1), the following species [V(dipic)(H₂asp)]⁺, [V(dipic)(Hasp)], [V(dipic)(asp)]⁻, [V(dipic)(asp)(OH)]²⁻, and [V(dipic)(asp)(OH)₂]³⁻ were found in the vanadium(III)–dipicolinic acid–aspartic acid system. In the vanadium(III)–dipicolinic acid–glutamic acid system [V(Hdipic)(H₂glu)]²⁺, [V(dipic)(H₂glu)]⁺, [V(dipic)(Hglu)], [V(dipic)(Hglu)(OH)]⁻, and [V(dipic)(Hglu)(OH)₂]²⁻ were observed. In the vanadium(III)–dipicolinic acid–cysteine system the complexes [V(dipic)(H₂cys)]⁺, [V(dipic)(Hcys)], [V(dipic)(cys)]⁻, and [V(dipic)(cys)(OH)]²⁻ were present. And finally, in the vanadium(III)–dipicolinic acid–histidine system the complexes [V(Hdipic)(Hhis)]²⁺, [V(dipic) (Hhis)]⁺[\mathrm{V}(\mathrm{dipic}) (\mathrm{Hhis})]^{+}, [V(dipic)(his)], [V(dipic)(his)(OH)]⁻, and [V(dipic)(his)(OH)₂]²⁻ were observed. The stability constants of these complexes were determined. The species distribution diagrams as a function of pH are briefly discussed.     

How environment affects drug activity: Localization,compartmentalization and reactions of a vanadium insulin-enhancing compound,dipicolinatooxovanadium(V)

The chemical and biological properties of a simple and traditional V(5+) coordination complex, dipicolinatooxovanadium(V) (abbreviated [VO₂dipic]^?), are described in order to present a hypothesis for a novel mode of action wherein a hydrophobic membrane environment plays a key role. Specifically, we propose that the compartmentalization and both chemical and biological transformations of vanadium-complexes direct whether beneficial or toxic effects will be observed with this class of compounds. This concept is based on the formation of high levels of uncontrollable reactive oxygen species (ROS) from one-electron reactions or alternative events possibly initiated by a two-electron reaction which may be directly or indirectly beneficial by reducing the high levels of ROS. The properties of dipicolinatooxovanadium(V) compounds in aqueous solution (D.C. Crans, et al., Inorg. Chem. 39 (2000) 4409–4416) are very different from those in organic solvents (S.K. Hanson, et al., J. Am. Chem. Soc. 131 (2009) 428–429) and these differences may be key for their mode of action. Since other vanadium complexes are known to hydrolyze upon administration, the low stability of the aqueous complex requires entrapment in hydrophobic environments for such a complex to exist sufficiently long to have an effect. The suggestion that the environment changes the reactivity of the compounds is consistent with the very different modes of action by which one complex act. In short, a novel hypothesis is presented for a mode of action of vanadium compounds based on differences in properties resulting from environmental conditions. These considerations are supported by recent evidence supporting a role for membranes and signal transduction events (D.A. Roess, et al. Chem. Biodivers. 5 (2008) 1558–1570) of the insulin-enhancing properties of these compounds.     

Absorption,transport and insulin-mimetic properties of bis(maltolato)oxovanadium (IV) in streptozotocin-induced hyperglycemic rats by integrated mass spectrometric techniques

The use of V(IV) complexes as insulin-enhancing agents has been increasing during the last decade. Among them, 3-hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven to be especially suitable as ligands for vanadyl ions. In fact, they have passed phase I and phase II clinical trials, respectively. However, the mechanism through which those drugs exert their insulin-mimetic properties is still not fully understood. Thus, the aim of this study is to obtain an integrated picture of the absorption, biodistribution and insulin-mimetic properties of the bis(maltolato)oxovanadium (IV) (BMOV) in streptozotocin-induced hyperglycaemic rats. For this purpose, BMOV hypoglycaemic properties were evaluated by monitoring both the circulating glucose and the glycohemoglobin, biomarkers of diabetes mellitus. In both cases, the results were drug concentration dependent. Using doses of vanadium at 3 mg/day, it was possible to reduce the glycaemia of the diabetic rats to almost control levels. BMOV absorption experiments have been conducted by intestinal perfusion revealing that approximately 35% of V is absorbed by the intestinal cells. Additionally, the transport of the absorbed vanadium (IV) by serum proteins was studied. For this purpose, a speciation strategy using high-performance liquid chromatography (HPLC) for separation and inductively coupled serum mass spectrometry, ICP-MS, for detection has been employed. The obtained HPLC-ICP-MS results, confirmed by MALDI-MS data, showed evidence that V, administered orally, is uniquely bound to transferrin in rat serum.     

Chiral self-dimerization of vanadium complexes on a SiO2 surface for asymmetric catalytic coupling of 2-naphthol: structure, performance, and mechanism

Vanadium monomers with chiral tridentate Schiff-base ligands were supported on SiO(2) through a chemical reaction with surface silanols, where we found a new chirality creation by the self-dimerization of the vanadyl complexes on the surface. The chiral self-dimerization and the role of surface silanols in the self-assembly were investigated by means of X-ray absorption near-edge structure (XANES), extended X-ray absorption fine structure (EXAFS), diffuse-reflectance ultraviolet/visible (DR-UV/VIS), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR), electron spin resonance (ESR), and density functional theory (DFT) calculations. The surface vanadyl complexes had a distorted square-pyramidal conformation with a V=O bond. FT-IR spectra revealed that the Ph-O moiety of Schiff-base ligands was converted to Ph-OH by a surface-concerted reaction between the vanadium precursors and surface SiOH groups. The Ph-OH in an attached vanadyl complex interacted with a COO moiety of another vanadyl complex by hydrogen bonding to form a self-dimerized structure at the surface. The interatomic distance of V-V in the surface self-assembly was evaluated to be 0.40 +/- 0.05 nm by ESR after O(2) adsorption. The self-dimerized V structure on SiO(2) was modeled by DFT calculations, which demonstrated that two vanadium monomers with Ph-OH linked together by two hydrogen bonds and their V=O groups were directed opposite to each other. The surface self-dimerization of the vanadium precursors fixes the direction of the V=O bond and the plane of the Schiff-base ligand. Thus, a new chiral reaction field was created by two types of chirality: the chiral Schiff-base ligand and the chiral V center. We have also found that the chiral self-dimerized vanadyl complexes exhibit remarkable catalytic performance for the asymmetric oxidative coupling of 2-naphthol: 96% conversion, 100% selectivity to 1,1'-binaphthol (BINOL), and 90% enantiomeric excess (ee). Increasing the vanadium loading on SiO(2) caused a dramatic swell of enantioselectivity, and the maximum 90% ee was observed on the supported catalyst with the full coverage of the vanadyl complex (3.4 wt % vanadium). This value is equivalent to the maximum ee reported in homogeneous catalysis for the coupling reaction. Furthermore, the supported vanadium dimers were reusable without loss of the catalytic performance. To our knowledge, this is the first heterogeneous catalyst for the asymmetric oxidative coupling of 2-naphthol.     

Ternary Complex Formation between Vanadium(III), Dipicolinic Acid and Picolinic Acid in Aqueous Solution

Ternary complex species formed by the V³⁺ cation with the picolinic acid (Hpic, HL) and dipicolinic acid (H₂dipic, H₂L) ligands in aqueous solutions have been studied potentiometrically (25 °C, I=3.0 mol⋅dm⁻³ KCl ionic medium) and by spectrophotometric measurements. Application of the least-squares computer program LETAGROP to the experimental emf (H) data, taking into account the hydrolytic V(III) species and the binary V³⁺–picolinic acid and V³⁺–dipicolinic acid complexes, shows that under the investigated conditions the following ternary complexes are formed: [V(dipic)(pic)], [V(dipic)(pic)(OH)]⁻ and [V(dipic)(pic)₂]⁻. The stability constants of the ternary complexes were determined by potentiometric measurements whereas the spectrophotometric measurements were done in order to obtain a qualitative characterization of the complexes formed in aqueous solution.     

Insulin-enhancing vanadium(III) complexes

Simple, high-yield, large-scale syntheses of the V(III) complexes tris(maltolato)vanadium(III), V(ma)3, tris(ethylmaltolato)vanadium(III), V(ema)3, tris(kojato)vanadium(III) monohydrate, V(koj)3-H2O, and tris(1,2-dimethyl-3-hydroxy-4-pyridinonato)vanadium(III) dodecahydrate, V(dpp)3-12H2O, are described; the characterization of these complexes by various methods and, in the case of V(dpp)3-12H2O, by an X-ray crystal structure determination, is reported. The ability of these complexes to normalize glucose levels in the STZ-diabetic rat model has been examined and compared with that of the benchmark compound BMOV (bis(maltolato)oxovanadium(IV)), an established insulin-enhancing agent.     

A new family of insulin-mimetic vanadium complexes derived from 5-carboalkoxypicolinates

The reaction of 5-carboalkoxypicolinic acid (5 ROpicH, R=Me, Et, iPr, sBu; 1 a-d) with vanadyl sulfate yielded the complexes [VO(H(2)O)(5 ROpic)(2)], 2 a-d, with H(2)O and one of the picolinato ligands in the equatorial positions, and the second picolinate occupying equatorial (N) and axial (O) positions. Reaction of 1 a with [NH(4)][VO(3)] yielded [NH(4)][VO(2)(5 MeOpic)(2)], [NH(4)]-3, in which the N functions of the picolinates are trans to the doubly bonded, cis-positioned oxo groups. Complexes 1 a.H(2)O, 1 b, 1 c, 2 a.3.5 H(2)O and [NH(4)]-3.4 H(2)O have been structurally characterised. A detailed pH-potentiometric solution speciation analysis of the system VO(2+)-1 a revealed a dominance of VO(5 OMepic)(2) between pH 2 and 6, with the same coordination pattern, evidenced by EPR spectroscopy, as in the crystalline solid state. In ternary systems containing physiological concentrations of the low molecular mass biogenic binders (B) lactate, oxalate, citrate or phosphate, ternary species of general composition VO(5 MeOpic)B dominate at physiological pH, with citrate being the most effective competitor for picolinate. All of the complexes trigger glucose uptake and degradation by simian virus modified mice fibroblasts at non-toxic concentrations (<100 microM), with 2 a, [VO(2)(pic)(2)](-) and [VO(2)(dipic)](-) being at least as effective as insulin. Vanadium uptake by the cells is most effective in the case of 2 a. 2 a also effectively inhibits free fatty acid release by rat adipocytes treated with epinephrine, thus mimicking the inhibition of lipolysis by insulin.     

DNA cleavage by new oxovanadium(IV) complexes of N-salicylidene alpha-amino acids and phenanthroline bases in the photodynamic therapy window

Oxovanadium(IV) complexes [VO(salmet)(B)] (1-3) and [VO(saltrp)(B)] (4-6), where salmet and saltrp are N-salicylidene-l-methionate and N-salicylidene-l-tryptophanate, respectively, and B is a N,N-donor heterocyclic base (viz. 1,10-phenanthroline (phen, 1, 4), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2, 5), and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3, 6)) are prepared and characterized and their DNA binding and photoinduced DNA cleavage activity studied. Complexes 1, 2, and 4 are structurally characterized by single-crystal X-ray crystallography. The molecular structure shows the presence of a vanadyl group in the VO3N3 coordination geometry. The dianionic alpha-amino acid Schiff base acts as a tridentate O,N,O-donor ligand in a meridional binding mode. The N,N-donor heterocyclic base displays a chelating mode of bonding with a N-donor site trans to the oxo group. The complexes show a d-d band in the range of 680-710 nm in DMF with a shoulder near 840 nm. They exhibit an irreversible oxidative cyclic voltammetric response near 0.8 V assignable to the V(V)/V(IV) couple and a quasi-reversible V(IV)/V(III) redox couple near -1.1 V vs SCE in DMF-0.1 M TBAP. The complexes show good binding propensity to calf thymus DNA giving binding constant values in the range from 5.2 x 10(4) to 7.2 x 10(5) M(-1). The binding site size, thermal melting, and viscosity data suggest DNA surface and/or groove binding nature of the complexes. The complexes show poor "chemical nuclease" activity in the dark in the presence of 3-mercaptopropionic acid or hydrogen peroxide. The dpq and dppz complexes show efficient DNA cleavage activity on irradiation with UV-A light of 365 nm via a mechanistic pathway involving formation of singlet oxygen as the reactive species. They also show significant DNA cleavage activity on photoexcitation in red light (>750 nm) by (1)O2 species. Observation of red-light-induced cleavage of DNA is unprecedented in the vanadium chemistry. The DNA cleavage activity is metal promoted as the ligands or vanadyl sulfate alone are cleavage inactive on photoirradiation at these wavelengths.     

Speciation of the Ternary Complexes of Vanadium(III)–Dipicolinic Acid with the Amino Acids Glycine,Proline, <Emphasis Type="Italic">α</Emphasis>-Alanine and <Emphasis Type="Italic">β</Emphasis>-Alanine Studied in 3.0 mol⋅dm<Superscript>−3</Superscript> KCl at 25 °C

In this paper we present speciation results for the ternary vanadium(III)–dipicolinic acid (H₂dipic) systems with the amino acids glycine (Hgly), proline (Hpro), α-alanine (Hα-ala), and β-alanine (Hβ-ala), obtained by means of electromotive forces measurements emf(H) using 3.0 mol⋅dm⁻³ KCl as the ionic medium and a temperature of 25 °C. The experimental data were analyzed by means of the computational least-squares program LETAGROP, taking into account hydrolysis of the vanadium(III) cation, the respective stability constants of the binary complexes, and the acid base reactions of the ligands, which were kept fixed during the analysis. In the vanadium(III)–dipicolinic acid–glycine system, formation of the ternary [V(Hdipic)(Hgly)]²⁺, [V(dipic)(Hgly)]⁺, [V(dipic)(gly)], [V(dipic)(gly)(OH)]⁻ and [V(dipic)(gly)(OH)₂]²⁻ was observed; in the case of the vanadium(III)–dipicolinic acid–proline system the ternary complexes [V(Hdipic) (Hpro)]²⁺, [V(dipic)(Hpro)]⁺, [V(dipic)(pro)] and [V(dipic)(pro)(OH)]⁻ were observed; in the vanadium(III)–picolinic acid–α-alanine were observed [V(Hdipic)(Hα-ala)]²⁺, [V(dipic) (Hα-ala)]⁺, [V(dipic)(αala)], [V(dipic)(α-ala)(OH)]⁻ and [V(dipic)(α-ala)(OH)₂]²⁻; and in the vanadium(III)–dipicolinic acid–β-ala system the complexes [V(dipic) (Hβ-ala)]⁺, [V(dipic)(β-ala)], [V(dipic)(β-ala)(OH)]⁻ and [V(dipic)(β-ala)(OH)₂]²⁻ were observed. Their respective stability constants were determined, and we evaluated values of Δlog ₁₀ K″ in order to understand the relative stability of the ternary complexes compared to the corresponding binary ones. The species distribution diagrams are briefly discussed as a function of pH.     

利用硫酸氧钒制备钒炭催化剂用于烟气脱硫

利用硫酸氧钒制备钒炭催化剂用于烟气脱硫。研究发现,负载在活性炭上的硫酸氧钒极易被氧化为五价钒硫酸盐,这些五价钒硫酸盐具有很高的氧化SO₂的活性,极大地促进了SO₂在活性炭上的脱除。而且,通过煅烧可以将五价钒硫酸盐分解为五价钒氧化物,最佳煅烧温度为500℃,由于煅烧后用于储存硫酸的微孔孔容增加,SO₂的吸附容量得到了进一步提高,由此表明,利用硫酸氧钒可以制备传统的V₂O₅/AC催化剂。为了获得完全氧化的钒物种,对煅烧后的催化剂进行了空气中预氧化,但由于含氧官能团的形成、炭载体的烧蚀以及钒的还原,预氧化不利于脱硫。此外,研究中得到初步证据证明脱硫过程中V₂O₅/AC催化剂中五价钒氧化物转变成了五价钒硫酸盐,结合五价钒硫酸盐所表现出的氧化SO₂的能力,推测SO₂在V₂O₅/AC上的脱除遵循以下机理:五价钒氧化物先转变为五价钒硫酸盐,后者催化氧化SO₂为硫酸。     

Oral administration of Bis(aspirinato)zinc(II) complex ameliorates hyperglycemia and metabolic syndrome-like disorders in spontaneously diabetic KK-A(y) mice: structure-activity relationship on zinc-salicylate complexes

In recent years, the number of patients suffering from diseases, such as cancer, apoplexy, osteoporosis, hypertension, and type 2 diabetes mellitus is increasing worldwide. Type 2 diabetes, a lifestyle-related disease, is recognized as a serious disease. Various types of pharmaceutics for diabetes have been used. Since the relationship between diabetes and biometals such as vanadium, copper, and zinc ions has been recognized for many years, we have been developing the anti-diabetic metal complexes as new candidates. We found that several zinc(II) (Zn) complexes exhibit glucose-lowering activity for treating type 2 diabetes. High doses of salicylates have been known to reverse hyperglycemia and hyperinsulinemia in type 2 diabetic patients. These findings strongly suggest that the combined use of Zn and salicylates achieves the synergism in treating type 2 diabetes. Because aspirin, acetyl salicylic acid, has a chelating ability, we used it as a ligand to Zn. Several Zn-salicylate complexes were prepared and their biological activities were examined in this study. The complexes with an electron-withdrawing group in the ligand exhibited higher in vitro insulinomimetic activity than those of Zn complexes with an electron-donating group in the ligand. When bis(aspirinato)Zn (Zn(asp)?) complex was orally administered on KK-A(y) mice with hereditary type 2 diabetes, the diabetic state was improved. In addition, this complex exhibited normalizing effects on serum adiponectin level and high blood pressure in metabolic syndrome. In conclusion, Zn(asp)? complex is newly proposed as a potent anti-diabetic and anti-metabolic syndrome agent.     

Vanadium complexes with mixed O,S anionic ligands derived from maltol: synthesis, characterization, and biological studies

Four mixed O,S binding bidentate ligand precursors derived from maltol (3-hydroxy-2-methyl-4-pyrone) have been chelated to vanadium to yield new bis(ligand)oxovanadium(IV) and tris(ligand)vanadium(III) complexes. The four ligand precursors include two pyranthiones, 3-hydroxy-2-methyl-4-pyranthione, commonly known as thiomaltol (Htma), and 2-ethyl-3-hydroxy-4-pyranthione, commonly known as ethylthiomaltol (Hetma), as well as two pyridinethiones, 3-hydroxy-2-methyl-4(H)-pyridinethione (Hmppt) and 3-hydroxy-1,2-dimethyl-4-pyridinethione (Hdppt). Vanadium complex formation was confirmed by elemental analysis, mass spectrometry, and IR and EPR (where possible) spectroscopies. The X-ray structure of oxobis(thiomaltolato)vanadium(IV),VO(tma)(2), was also determined; both cis and trans isomers were isolated in the same asymmetric unit. In both isomers, the two thiomaltolato ligands are arranged around the base of the square pyramid with the V=O linkage perpendicular; the vanadium atom is slightly displaced from the basal plane [V(1) = 0.656(3) A, V(2) = 0.664(2) A]. All of the new complexes were screened for insulin-enhancing effectiveness in streptozotocin-induced diabetes in rats, and VO(tma)(2) was profiled metabolically for urinary vanadium and ligand clearance by GFAAS and ESIMS, respectively. The new vanadium complexes did not lower blood glucose levels acutely, possibly because of rapid dissociation and excretion.     

A new concept: the use of vanadium complexes in the treatment of diabetes mellitus

In the 21st century, patients suffering from diabetes mellitus (DM), a lifestyle-related disease, will increase more than in the 20th century. DM is threatening because of the development of many severe secondary complications, including atherosclerosis, microangiopathy, renal dysfunction and failure, cardiac abnormalities, diabetic retinopathy, and ocular disorders. Generally, DM is classified as either insulin-dependent type 1 or noninsulin-dependent type 2 DM. Type 1 DM is treated only by daily insulin injections; type 2 DM is treated by several types of synthetic therapeutic substances together with a controlled diet and physical exercise. Even with these measures, the daily necessity for several insulin injections can be painful both physically and mentally, whereas the synthetic therapeutic substances used over the long term often have side effects. For those reasons, the creation and development of a new class of pharmaceuticals for treatment of DM in the 21st century would be extremely desirable. In the last half of the 20th century, investigations of the relationships among diseases and micronutrients, such as iron, copper, zinc, and selenium, have been numerous. Research into the development of metallopharmaceuticals involving the platinum-containing anticancer drug, cisplatin, and the gold-containing rheumatoid arthritis drug, auranofin, has also been widespread. Such important findings prompted us to develop therapeutic reagents based on a new concept to replace either insulin injections or the use of synthetic drugs. After many trials, we noticed that vanadium might be very useful in the treatment of DM. Before the discovery of insulin by Banting and Best in 1921 and its clinical trial for treating DM, the findings in 1899, in which orally administered sodium vanadate (NaVO(3)) was reported to improve human DM, gave us the idea to use vanadium to treat DM. However, it has taken a long time to obtain a scientific explanation as to why the metal ion exhibits insulin-mimetic or blood-glucose lowering effects in in vitro and in vivo experiments. After investigations from many perspectives involving biochemistry and bioinorganic chemistry, vanadyl sulfate (VOSO(4)) and its complexes with several types of ligands have been proposed as useful for treating DM in experimental diabetic animals. On the basis of a mechanistic study, this article reports on recent progress regarding the development of antidiabetic vanadyl complexes, emphasizing that the vanadyl ion and its complexes are effective not only in treating or relieving both types of DM but also in preventing the onset of DM.