Vanadyl-biguanide complexes as potential synergistic insulin mimics

Vanadium has well-documented blood-glucose-lowering properties both in vitro and in vivo. The design of new oxovanadium(IV) coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biguanides, most importantly metformin, are oral hypoglycemic agents used today to treat type 2 diabetes mellitus. In this study, biguanide, metformin, and phenformin, all biguanides, were coordinated to oxovanadium(IV) to form potential insulin-enhancing compounds. Highly colored, air-stable, bis(biguanidato)oxovanadium(IV), [VO(big)2], bis(N'N'-dimethylbiguanidato)oxovanadium(IV), [VO(metf)2], and bis(beta-phenethyl-biguanidato)oxovanadium(IV), [VO(phenf)2], were prepared. Solvation with dimethylsulfoxide occurred with VO(metf)2 to form a six-coordinate complex. Precursor ligands and oxovanadium(IV) coordination complexes were characterized by infrared spectroscopy, mass spectrometry, elemental analyses, magnetic susceptibility, and, where appropriate, 1H NMR spectroscopy. Biological testing with VO(metf)2, a representative compound, for insulin-enhancing potential included acute (72 h) administration, both by intraperitoneal (i.p.) injection and by oral gavage (p.o.) in streptozotocin (STZ)-diabetic rats. VO(metf)2 administration resulted in significant blood-glucose lowering at doses of 0.12 mmol kg-1 i.p. and 0.60 mmol kg-1 p.o. (previously established as ED50 doses for organically chelated oxovanadium(IV) complexes); however, no positive associative effects due to the presence of biguanide in the complex were apparent.     

One and Two Dimensional Pulsed Electron Paramagnetic Resonance Studies of in vivo Vanadyl Coordination in Rat Kidney

The biological fate of a chelated vanadium source is investigated by/n vivo spectroscopic methods to elucidate the chemical form in which the metal ion is accumulated. A pulsed electron paramagnetic resonance study of vanadyl ions in kidney tissue, taken from rats previously treated with bis(ethylmaltolato)oxovanadium(IV) (BEOV) in drinking water, is presented. A combined approach using stimulated echo (3-pulse) electron spin echo envelope modulation (ESEEM) and the two dimensional 4-pulse hyperfine sublevel correlation (HYSCORE) spectroscopies has shown that at least some of the VO²⁺ ions are involved in the coordination with nitrogen-containing ligands. From the experimental spectra, a 4N hyperfine coupling constant of 4.9 MHz and a quadrupole coupling constant of 0.6 + 0.04 MHz were determined, consistent with amine coordination of the vanadyl ions. Study of VO-histidine model complexes allowed for a determination of the percentage of nitrogen-coordinated VO²⁺ ions in the tissue sample that is found nitrogen-coordinated. By taking into account the bidentate nature of histidine coordination to VO²⁺ ions, a more accurate determination of this value is reported. The biological fate of chelated versus free (i.e. salts) vanadyl ion sources has been deduced by comparison to earlier reports. In contrast to its superior pharmacological efficacy over VOSO4, BEOV shares a remarkably similar biological fate after uptake into kidney tissue.     

Model complexes for amavadine,a vanadium natural product

Amavadine is a vanadium natural product from the mushroom Amanita muscaria. Earlier reports have characterized the compound as a vanadyl (VO²⁺) complex with two N-hydroxy-αα-iminodipropionic acid ligands, but no hypothesis as to its function has yet been put forward. We report here the synthesis, isolation, and properties of bis(iminodiacetato)oxovanadium(IV) and bis(αα-iminodipropionato)oxovanadium(IV). The complex bis(ββ-iminodipropionato)oxovanadium(IV) has been prepared in solution. These complexes serve as models for Amavadine. The structures of the models are analogous to that of Amavadine, with two bidentate, singly charged ligands bonding through one oxygen and one nitrogen atom. The visible spectra suggest the possibility of 1:1 complexes in solution in addition to the 2:1 ligand to metal complexes. Preliminary electrochemical data suggest reversible V(IV) ? V(III) couples.     

Synthesis and characterization of mononuclear oxovanadium(IV) complexes and their enzyme inhibition studies with a carbohydrate metabolic enzyme phosphodiesterase I

The increasing interest in vanadium coordination chemistry is based on its well-established chemical and biological functions. A beta-diketonato complex of oxovanadium(IV) is known to be having numerous catalytic applications and also exhibits promising insulin mimetic properties. In continuation of our structure activity relationship studies of metal complexes, we report herein the synthesis and characterization of the vanadium complexes of beta-diketonato ligand system with systematic variations of electronic and steric factors. Two complexes, VO(tmh)(2) (tmh = 2,2,6,6,-tetramethyl-3,5-heptanedione), and VO(hd)(2) (hd = 3,5-heptanedione) were synthesized and characterized by using different spectroscopic techniques. Elemental and mass spectral analysis supports the presence of two beta-diketonato ligands per VO(2+) unit. UV-Vis spectra in different solvents indicate coordination of coordinating solvent molecules at sixth position resulting in red shift of the band I transition. NMR and IR spectra reveal binding of coordinating solvent molecule at vacant sixth position trans to oxo group without releasing beta-diketonato ligands. Enzyme inhibition studies of these and other related oxovanadium(IV) complexes with beta-diketonato ligand system are conducted with snake venom phosphodiesterase I (SPVDE). All of these complexes showed significant inhibitory potential and were found to be non-competitive inhibitors against this enzyme.     

Oxovanadium(IV) and dioxouranium(VI) complexes with thiocarbohydrazones

Oxovanadium(IV) and dioxouranium(VI) complexes with thiocarbohydrazones have been prepared in an ethanolic medium and characterised by elemental analysis and molecular weight determination. They have 1:1 stoichiometry. The IR observations suggest that the ligands have coordinated through azomethine nitrogen atoms and reacted through hydroxy groups. The v(MN) and v(MO) vibrations have been assigned. The PMR spectral information supports the IR inference. The oxovanadium(IV) complexes show magnetic moments in the range of 1.74–1.94 B.M. The electronic spectra have been interpreted in the light of the BG model. Various NSH parameters have been calculated. The ESR spectra also render support for the spectral information. On the basis of this information it is suggested that oxovanadium(IV) complexes exhibit coordination number five and dioxouranium coordination number six.     

Structural characterization of pentadentate salen-type Schiff-base complexes of oxovanadium(IV) and their use in sulfide oxidation

Pentadentate Schiff-base complexes of oxovanadium(IV), the ligands of which were derived from salicylaldehyde derivatives with a variety of substituents and two kinds of amines (2,2^′-bis(aminoethyl)amine and 3,3^′-bis(aminopropyl)amine), were prepared, and their coordination geometries in the solid state were determined by X-ray diffraction and IR measurements and those in CH₂Cl₂ by EPR measurements. They were found to retain distorted octahedral coordination in the solid state. They showed the structural change depending on the type of the substituent. The complexes which reacted with tert-butylhydroperoxide converted methyl phenyl sulfide to the corresponding sulfoxide at lower rates of reaction than tridentate N-salicylidene-2-aminoethanolato oxovanadium(IV) ([VO(salae)]) and tetradentate (N,N^′-bis(salicylidene)ethylenediaminato)oxovanadium(IV) ([VO(salen)]).     

Interactions of oxovanadium(IV) and the quinolone family member--ciprofloxacin

The interactions of quinolone ciprofloxacin (cfH) and oxovanadium(IV) were studied by various methods. Green crystals of a complex [V(IV)O(cf)(2)(H(2)O)] were isolated and the molecular connectivities established, although the crystal structure was not perfectly refined due to the instability of the crystals. Based on a plausible interpretation of the data sets, two cf anions bidentately coordinate to a vanadyl cation through carboxylate and carbonyl oxygen atoms; in addition, there is a water molecule in the coordination sphere. Solution techniques (cyclic voltammetry, electronic and electron paramagnetic resonance spectroscopy, potentiometric measurements) confirmed the presence of various species in the solution, the composition of which strongly depends on the conditions in the system. The antibacterial activity of the complex against various microorganisms was tested and it was established that its activity is similar to that of free ciprofloxacin.     

Preparation and characterization of oxovanadium(IV), acetatomanganese(III), chloroiron(III), nickel(II), copper(II), zinc(II) and palladium(II) complexes of 3,3′-(1,2-phenylenediimino)diacrolein

The oxovanadium(IV), acetatomanganese(III), chloroiron(III), nickel(II), copper(II), zinc(II) and palladium(II) of 3,3′-(1,2-phenylenediimino)diacrolein were prepared and investigated by means of mass, electronic, vibrational, NMR and ESR spectroscopy as well as magnetic susceptibility measurements. The acetatomanganese(III) and chloroiron(III) complexes were confirmed to be of high spin type. The absorption bands appearing in the energy range greater than 23 000 cm⁻¹ were attributed to π→π^* transitions within a ligand molecule and charge- transfer transitions from metal to ligand. The metal complexes assume the square-planar configuration type since the ligand-field bands were detected in the 12 700–18 500 cm⁻¹ region. Strong bands appearing at 1601 and 1627 cm⁻¹ were assigned to the CC and CO stretching vibrational modes, respectively, and were shifted to lower frequency upon metal-coordination. A VO stretching band was observed at 982 cm⁻¹ for the oxovanadium(IV) complex and a CO stretching band was observed at 1547 cm⁻¹ for the acetatomanganese(III) complex. Upon complex formation the amine proton signal is found to vanish and the aldehydic methine proton signal in the lowest field is shifted upfield for the nickel(II), zinc(II) and palladium(II) complexes. ¹³C NMR spectra support the coordination structure of the complexes which is revealed by ¹H NMR spectra. As judged by the spin Hamiltonian parameters, the oxovanadium(IV) complex is of a square- planar type with an unpaired electron in the d_xy orbital and the copper(II) complex assumes a distorted square-planar coordination due to the presence of five- and six-membered chelate rings with an unpaired electron in the d_x2−y2 orbital.     

Renaturation effects of cis and trans platinum II and IV compounds on calf thymus deoxyribonucleic acid.

The effects of cis dichlorodiammine platinum [cis Pt(II)], trans dichlorodiammine platinum (trans Pt(II)], cis tetrachlorodiammine platinum [cis Pt(IV)], trans tetrachlorodiammine platinum [trans Pt(IV)], and ethylenediaminedichloride platinum [Pt(II)en] on the absorption spectra, and thermal hyper- and hypochromicity of calf thymus DNA were investigated. Platinum-induced renaturation was studied as one parameter of interstrand cross-linking. Based on a DNA cross-linking hypothesis, the tumor-inhibitory platinum compounds cis Pt(II), cis Pt(IV) and Pt(II)en would be expected to induce renaturation following thermal denaturation, whereas the ineffective drugs, trans Pt(II) and trans Pt(IV) would not. All five bind to DNA in such a way as to induce renaturation. However, cis Pt(IV) requires at least a 3- to 4-fold longer incubation time than is required by the other compounds to form the coordination bonds necessary for renaturation. Maximum renaturation with all compounds was observed at a molar Pt/base ratio of 0.05 except cis Pt(IV), with which it was 0.25. The rate of the formation of the platinum-coordinated cross-links by fresh cis Pt(II) suggests two reactions or types of reactions occur. The first is rapid and destabilizes the DNA helix, whereas the second is slow and responsible for renaturation following thermal denaturation. These results suggest that cis Pt(IV) may be activated cellularly and that cross-linking is not the primary mechanism of action of the tumor-inhibitory platinum compounds.     

Synthesis,characterization and catalytic oxidations of oxovanadium(IV), oxotitanium(IV) and dioxomolybdenum(VI) complexes with chiral imines of L-amino acids

Representative oxovanadium(IV), oxotitanium(IV), and dioxomolybdenum(VI) complexes of N-salicylidene-L-amino acids (the amino acids are: valine, leucine, except for Mo(VI), and histidine) have been synthesized and characterized by various spectroscopic techniques. It has been found that while in the histidine complexes of titanium(IV) and vanadium(IV) the amino acid residue is bound in the expected glycine-like mode, in the molybdenum(VI) complex it is bound in the unusual histamine-like mode. Also, the structure of this molybdenum(VI) complex contains imidazolate-bridged polymeric units in the solid state, while the carboxyl group of the amino acid residue is protonated. In solution the polymeric structure is cleaved and the monomers contain carboxylate and protonated imidazole groups at the histidine residue. The histamine-like structure of the histidine complex was probcd by comparison with that of the chiral dioxomolybdenum(VI) complex of N-salicylidene-L-histidinol. While the structure of the metal centers is six-coordinate for the dioxomolybdenum(VI) complexes and the histidine complexes of oxotitanium(IV) and oxovanadium(IV), it is likely that the complexes of the latter metals derived from nonpolar amino acids do not achieve coordination numbers higher than five. The present oxometal complexes are catalytically active in the sulfoxidation of sulfides and in the epoxidations of activated olefins by tert-butyl hydroperoxide, but in general exhibit a low degree of asymmetric induction in these reactions.     

Detection of oxovanadium(IV) and characterization of its ligand environment in subcellular fractions of the liver of rats treated with pentavalent vanadium(V)

Tetravalent oxovanadium(IV) was detected in subcellular fractions of liver by ESR spectroscopy after i.p. injection of pentavalent vanadium(V) as sodium vanadate into rats for three days. This indicates that the metal ion was reduced from the pentavalent state to oxovanadium(IV). The ligand environment around this oxovanadium center was characterized using ESR parameters (g_o and A_o) and the empirical bonding coefficients calculated from the ESR parameters. These values indicate that most of the ligand atoms around the oxovanadium(IV) are oxygens and that the metal may exist in a protein-bound form.     

Polyoxovanadates: The missing link between simple paramagnets and bulk magnets?

Oxovanadium clusters provide novel examples of large magnetic clusters, which may showin nuce the typical behavior of bulk magnetic materials.The paper reviews the magnetic properties of V₁₅, comprising fifteen oxovanadium(IV); V₁₄, comprising fourteen oxovanadium(IV); V₃₊₁, comprising three localized oxovanadium(IV), six localized oxovanadium(V), and one oxovanadium(IV) delocalized over three sites; V₄₊₂ and V₄₊₄ which comprise four localized and two and four delocalized oxovanadium(IV), respectively. The different observed magnetic behaviors are discussed on the basis of several models of different sophistication.     

Enhancement of insulin signaling pathway in adipocytes by oxovanadium(IV) complexes

Recently, we have found that some oxovanadium(IV) complexes are potent insulin-mimetic compounds for treating both type I and type II diabetic animals. However, the functional mechanism of oxovanadium(IV) complexes is not fully understood. In this report, we have shown that oxovanadium(IV)-picolinate complexes such as VO(pa)(2), VO(3mpa)(2), and VO(6mpa)(2) act on the insulin signaling pathway in 3T3-L1 adipocytes. Among them, VO(3mpa)(2) was found to be the highest potent activator in inducing not only the phosphotyrosine levels of both IRbeta and IRS but also the activation of downstream kinases in the insulin receptor, such as Akt and GSK3beta, which in turn translocated the insulin-dependent GLUT4 to the plasma membrane. Then, we examined whether or not oxovanadium(IV)-picolinates exhibit the hypoglycemic activity in STZ-induced diabetic mice, and found that VO(3mpa)(2) is more effective than the others in improving the hyperglycemia of the animals. Our present data indicate that both activation of insulin signaling pathway, which follows the GLUT4 translocation to the plasma membrane, and enhancement of glucose utilization by oxovanadium(IV) complexes cause the hypoglycemic effect in diabetic animals.     

Synthesis and in vitro cytotoxicity of cis,cis,trans-diamminedichloridodisuccinatoplatinum(IV)-peptide bioconjugates

The synthesis and characterization of four Pt(IV)-peptide conjugates, containing one or two peptides in the axial position, designed for the purpose of targeted drug delivery to tumor cells, are described. The precursor cis,cis,trans-diamminedichloridodisuccinatoplatinum(IV) was coupled in the last step of standard solid-phase peptide synthesis (SSPS) with an analogue of neurotensin (pseudo-neurotensin = Lys-Lys-Pro-Tyr-Ile-Leu) and with octreotate (D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OH), an analogue of somatostatin, respectively. For all peptides, the SSPS reactions afforded both mono- and diconjugated Pt-peptide species, which were separated and purified by RP-HPLC. The two couples of conjugates, together with the precursor, were tested as cytotoxic agents towards different cancer cell lines. In general all conjugates are good inhibitors of cellular proliferation when compared to a nontargeting platinum(IV) parent compound, so that its relatively low cytotoxicity is greatly improved by addition of the peptides.     

The influence of a new vanadium compound, bis(2,2'-bipyridine)oxovanadium(IV) sulphate on liver golgi complexes from control and streptozotocin-diabetic rats.

Among the previously studied organic vanadium derivatives showing an anti-diabetic action, we investigated a new complex, bis(2,2'-bipyridine)oxovanadium(IV) sulphate. We tested its ability to normalise parameters previously described for streptozotocin (STZ)-diabetes, such as lower yields of Golgi-rich membrane fraction isolation, decreased activity of Golgi membrane marker enzyme - galactosyltransferase (GalT) - and altered morphology of rat liver Golgi complexes. Oral application as a drinking solution of 1.8 mmol bis(2,2'-bipyridine)oxovanadium(IV) (dissolved in 0.09 M NaCl) caused a similar dispersion of GalT activities in both vanadium treated groups, control and diabetic. Very low activities of the enzyme (characteristic for untreated diabetes) we found only in approximately 35 % of the STZ-diabetic rats treated with the new vanadium compound. The morphology of liver Golgi complexes in diabetic rats treated with bis(2,2'-bipyridine)oxovanadium(IV) sulphate was improved, which manifested itself in the reappearance of vacuoles with VLDL and coated and uncoated secretory vesicles. In view of biochemical and morphological parameters of normalised diabetic rat liver Golgi apparatus, the new vanadium complex was more effective than bis(oxalato)oxovanadium(IV) or bis(kojato)oxovanadium(IV), but in our experimental model, the best anti-diabetic, orally applied drug was the bis(maltolato)oxovanadium(IV) previously investigated.     

Spectral characterization of vanadium-transferrin systems

The preparation procedure of vanadium(III) transferrin and its stability are confirmed to be as previously reported. The electronic spectra of vanadium(III), oxovanadium(IV), and vanadium(V) transferrin derivatives are comparatively discussed. A band in the near infrared of the oxovanadium(IV) derivative is observed for the first time.     

Uptake and metabolic effects of insulin mimetic oxovanadium compounds in human erythrocytes

The uptake of the oxidation products of two oxovanadium(IV) compounds, [N,N'-ethylenebis(pyridoxylaminato)]oxovanadium(IV), V(IV)O(Rpyr(2)en), and bis-[3-hydroxy-1,2-dimethyl-4-pyridinonato]oxovanadium(IV), V(IV)O(dmpp)(2), by human erythrocytes was studied using (51)V and (1)H NMR and EPR spectroscopy. V(IV)O(Rpyr(2)en) in aerobic aqueous solution is oxidized to its V(V) counterpart and the neutral form slowly enters the cells by passive diffusion. In aerobic conditions, V(IV)O(dmpp)(2) originates V(V) complexes of 1:1 and 1:2 stoichiometry. The neutral 1:1 species is taken up by erythrocytes through passive diffusion in a temperature-dependent process; its depletion from the extracellular medium promotes the dissociation of the negatively charged 1:2 species, and the protonation of the negatively charged 1:1 species. The identity of these complexes is not maintained inside the cells, and the intracellular EPR spectra suggest N(2)O(2) or NO(3) intracellular coordinating environments. The oxidative stress induced by the oxovanadium compounds in erythrocytes was not significant at 1mM concentration, but was increased by both vanadate and oxidized V(IV)O(dmpp)(2) at 5mM. Only 1mM oxidized V(IV)O(dmpp)(2) significantly stimulated erythrocytes glucose intake (0.75+/-0.13 against 0.37+/-0.17mM/h found for the control, p<0.05).     

Synthesis, X-ray structure, and anti-leukemic activity of oxovanadium(IV) complexes

In a systematic effort to identify and develop effective anticancer agents, four oxovanadium(IV) complexes with 1,10-phenanthroline (Phen) or 4,7-dimethyl-1,10-phenanthroline (Me2-Phen) as ligand(s) were synthesized and characterized. Among the four oxovanadium(IV) complexes synthesized, the crystal structure of the bis(phenanthroline)oxovanadium(IV) complex bis(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Phen)2], compound 1) has been determined. Compound 1 crystallized in the space group P2(1)/n with unit cell parameters a = 14.2125(17) A, b = 10.8628(13) A, c = 20.143(2) A, alpha = 90 degrees, beta = 102.569(2) degrees, gamma = 90 degrees, V = 3035.3(6) A3, and Z = 4. The refinement of compound 1 by full-matrix least-squares techniques gave an R factor of 0.0785 for 4356 independent reflections. The structure contains two enantiomorphous molecules, lambda and delta, which are related by an inversion center. Compound 1 exhibited 3.5-fold more potent cytotoxic activity against NALM-6 human leukemia cells than the mono(phenanthroline)oxovanadium(IV) complex (diaqua)(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Phen)(H2O)2], compound 2) (IC50 values: 0.97+/-0.10 microM versus 3.40+/-0.20 microM: P=0.0004). Methyl substitution in the phenanthroline ligand enhanced the anti-leukemic activity of the mono(phenanthroline)oxovanadium(IV) complex 4.4-fold (IC50 values: 0.78+/-0.10 microM, compound 4, versus 3.40+/-0.20 microM, compound 2; P=0.0003) and the anti-leukemic activity of the bis(phenanthroline)oxovanadium(IV) complex 5.7-fold (IC50 values: 0.17+/-0.02 microM, compound 3, versus 0.97+/-0.10 microM, compound 1; P=0.001). The leading oxovanadium compound, bis(4,7-dimethyl-1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Me2-Phen)2], compound 3) triggered the production of reactive oxygen species (ROS) in human leukemia cells, caused G1-arrest and inhibited clonogenic growth at nanomolar concentrations.     

Spectroscopic characterization of amino acid and amino acid ester-Schiff-base complexes of oxovanadium and their catalysis in sulfide oxidation

α-Amino acid Schiff-base complexes of oxovanadium(IV), whose ligands have amino acid side chains with coordinating functional groups, retained coordination geometries in which the amino acid side chains were probably coordinated in the axial position with a phenolate oxygen, a carboxylate oxygen, an imine nitrogen, and a solvent being bound in the equatorial plane. As for amino acid ester Schiff-base complexes, the amino acid side chains were coordinated in the equatorial plane in the place of the carboxyl group in the case of the amino acid Schiff-base complexes. The amino acid Schiff-base complexes of oxovanadium(V) were present as dimers in dichloromethane. Peroxo complexes prepared from the Schiff-base complexes of oxovanadium(V) converted methyl phenyl sulfide to the corresponding sulfoxide in 80-90% yield in CDCl₃ and in 30-70% yield in CD₃OD in 30 min. They converted the sulfide in a stereoselective manner yielding the sulfoxide in small enantiomeric excess (5-20%).     

A new salicylic acid-derivatized kojic acid vanadyl complex: synthesis, characterization and anti-diabetic therapeutic potential

The molecular mechanisms of vanadium toxicity suggest that incorporation of antioxidant groups in the structure of vanadium complexes could be a preferable strategy in designing novel hypoglycemic vanadium complexes with proper efficacy and safety. By conjugating a pyrone skeleton to provide a coordination group and antioxidative motifs, we synthesized a novel complex of bis ((5-hydroxy-4-oxo-4 H-pyran-2-yl) methyl 2-hydroxy- benzoatato) oxovanadium (IV) (BSOV). Evaluation of the anti-diabetic effects of BSOV using streptozotocin (STZ)-induced diabetic rats with bis (maltolato) oxovanadium (BMOV) as a positive control showed that BSOV effectively lowered blood glucose level, ameliorated damages of hepatic and renal function in diabetic rats and improved lipid metabolism. The signs of potential alteration of renal function caused by BSOV and BMOV were observed and are discussed. Overall, the experimental results suggest BSOV as a potent hypoglycemic agent and further studies using this strategy for anti-diabetic agents.