Preparation and characterisation of oxovanadium(IV) complexes derived from 2,6-diformyl-4-methylphenol and l-His and l-Ala. Spectroscopic study of the system VO + BDF-His

By reaction of 2,6-diformyl-4-methylphenol (BDF) with the amino acids l-His and l-Ala in the presence of VOCl₂, two new oxovanadium(IV) complexes with the ligand obtained by the 1:2 condensation of BDF with the amino acids, BDF-His and BDF-Ala, were synthesised. The compounds were characterised in the solid state by elemental analyses, IR, CD and magnetic susceptibility measurements, and in the mother liquor by EPR. In water-containing solutions, BDF-Ala and BDF-His partially hydrolyse but the degree of Schiff base formation increases upon addition of VOSO₄. The equilibria in the system V^IVO²⁺ + BDF-His were studied by spectroscopic methods (EPR, CD and UV-Vis) in the pH range 1.5-12. The coordination behaviour of the ligand changes as the pH increases, leading to the formation of four main species all involving O_phen as donor atom. Plausible binding modes are discussed based on the spectroscopic results.     

Ternary oxovanadium(IV) complexes with amino acid-Schiff base and polypyridyl derivatives: synthesis, characterization, and protein tyrosine phosphatase 1B inhibition

To investigate the structure-activity relationship of vanadium complexes in inhibiting protein tyrosine phosphatase1B (PTP1B), eight mixed-ligand oxovanadium(IV) complexes, [V^IVO(SalAla)(NN)] (H₂SalAla for salicylidene alanine, NN for N,N′-donor heterocyclic base, namely, 2,2′-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq, 3), dipyrido[3,2-a:2′,3′-c]phenazine (dppz, 4)), [V^IVO(SalLys)(dpq)] (5), [V^IVO(SalLys)(dppz)] (6), [V^IVO(SalAsp)(dppz)], (7) and [V^IVO(SalTrp)(dppz)] (8)), of which 3-8 are new, have been prepared and characterized by elemental analysis, infrared, UV-visible, electrospray ionization mass spectrometry and conductivity. The molar conductance data confirmed the non-electrolytic nature of the complexes in DMSO solution. The coordination in [V^IVO (SalAla)(phen)] (2) was confirmed by X-ray crystal structure analysis. The oxidation state of V(IV) with d¹ configuration in 2 was confirmed by EPR. The speciation of VO-SalAla-phen in aqueous solution was investigated by potentiometric pH titrations. The results indicate that the main species are two ternary complexes at the pH range 7.0-7.4. Biochemical assays demonstrate that the mixed-ligand oxovanadium(IV) complexes are potent inhibitors of PTP1B with IC₅₀ values in the range of 62-597 nM, approximately 3-10 fold weaker in potency than those of similar mixed-ligand oxovanadium(IV) complexes of salicylidene anthranilic acid (SAA) derivative with polypyridyl ligands, except complex 8, which exhibits comparable or better inhibition activity than those of the mixed-ligand oxovanadium(IV) complexes of SAA derivative with polypyridyl ligands. The results demonstrate that the structures of vanadium complexes influence the PTP1B inhibition activity. Kinetics assays reveal that complex 2 inhibits PTP1B in a competitive manner.     

Polyoxovanadates with organic ligands

Polyoxovanadates are inhibitors to various phosphate-metabolizing enzymes. The question arises of how the cluster is bound to the protein matrix. This paper describes oxovanadates with carboxylate and hydroxide ligands in the periphery of the cluster, which may be considered to model oxovanadate binding to carboxylic and alcoholic side-chain functions of the protein. Examples for complexes carrying alkoxo ligands dealt with in this article are dinuclear vanadate(V) esters, and hexa-, octa- and decanuclear, mixed-valence (V^V/V^IV) clusters, the latter related to decavanadate. The possible role of dimeric vanadate esters as transition state anologues in enzymatic phosphoester cleavage is addressed. Examples for carboxylate complexes are the mononuclear, seven-coordinate mixed anhydride between orthovanadic acid and pivalic acid, containing the carboxylate in the bidentate mode, tetra-, penta- and hexanuclear V^IV/V^V clusters with bridging carboxylate, and trinuclear V^IV and V^II/V^III clusters, bridged by carboxylates and trebly bridged by O^2–. Special attention is given to a comparison of the bowls containing a V₄(-O)₃(-OH)(O₂CR)₄ and V₄(-O₄(O₂CR)₄ core, respectively, which can accomodate a K⁺ or a NO ₃ ^– .⁵¹V NMR spectroscopy is shown to be a useful tool, in many cases, for the vanadium speciation of complex systems.     

On the interaction of oxovanadium (IV) with homocysteine

The interaction of the VO²⁺ cation with homocysteine, was investigated by electron absorption spectroscopy in aqueous solution at different metal-to-ligand ratios. The direct reduction of vanadate(V) solutions with homocysteine was also investigated. The results suggest that the interaction is different from that found in the case of cysteine and occurs through pairs of amino and carboxylate groups of the amino acid. The interaction of VO²⁺ with homocystine, the oxidation product of homocysteine, was also analyzed. The interest of the results in relation to vanadium metabolism and detoxification is briefly discussed.     

Studies of the oxovanadium(IV)—oxalate system: syntheses and crystal structures of binuclear (Ph4P)2[(VO)2(H2O)2(C2O4)3]·4H2O and of the one-dimensional chain material, (Ph4P)[VOCl(C2O4)]

The hydrothermal reactions of (Ph₄P)[VO₂Cl₂] and H₂C₂O₄ at 150 and 125°C yield (Ph₄P)₂[V₂O₂(H₂O)₂(C₂O₄)₃]·4H₂O (1) and (Ph₄P)[VOCl(C₂O₄)] (2), respectively. The structure of the molecular anion of 1 consists of a binuclear unit of oxovanadium(IV) octahedra bridged by a bisbidentate oxalate group. The VO₆ coordination geometry at each vanadium site is defined by a terminal oxo group, an aquo ligand, and four oxygen donors — two from the bisbidentate bridging oxalate and two from the terminal bidentate oxalate. The structure of 2 consists of discrete Ph₄P⁺ cations occupying regions between [VOCl(C₂O₄)]⁻_∞ spiral chains. The structure of the one-dimensional anionic chain exhibits V(IV) octahedra bridged by bisbidentate oxalate groups. Crystal data: 1·4H₂O, monoclinic P2₁/n, A = 12.694(3), B = 12.531(3), C = 17.17(3) Å, β = 106.32(2)°, V = 2621.3(13) ų, Z = 2, D_calc = 1.501 g cm⁻³, structure solution and refinement converged at a conventional residual of 0.0518; 2, tetragonal P4₃, A = 12.145(2), C = 15.991(3) Å, V = 2358.7(12) ų, Z = 4, R = 0.0452.     

Oxovanadium(IV) complexes with Knoevenagel Schiff base condensate as impending chemotherapeutic agents: Synthesis,characterization, biological screening and anti-proliferative assay

Two novel oxovanadium(IV) complexes [VOL1]SO₄ (1) and [VOL2]SO₄ (2) containing Knoevenagel condensate Schiff base ligand (L1/L2) have been synthesized and characterized by physical, spectral and analytical methods. These complexes are reported as ionic in nature on the basis of elemental composition and molar conductance, and possess square pyramidal geometry around the central metal ions. The binding interactions of (1) and (2) with calf thymus DNA (CT DNA) were explored by absorption spectrophotometric titration, cyclic voltammetry data and viscosity measurements. The calculated intrinsic binding constant values (K_b) for (1) and (2) obtained from UV–Vis absorption studies are 0.4 × 10⁵ and 5.6 × 10⁵ (M⁻¹) respectively. These experimental results indicate that (1) and (2) are intercalative binders and avid binder to CT DNA with different affinities. These complexes exhibit significant oxidative cleavage of supercoiled plasmid (pUC18) DNA in the presence of activators. In particular, the in vitro antimicrobial efficacy of oxovanadium(IV) complexes reveal that they are more active than free ligands. Besides, the in vitro cytotoxic effect of the titled complexes were examined on a bundle of human tumor cell lines such as MCF-7 and HeLa cancerous cell lines by the MTT method. Interestingly, complex (2) exhibits more potent cytotoxic activity than the other complex and standard drug (cisplatin). The mode of cell death was assessed by Hoechst 33258 staining morphological studies.     

Novel 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes to investigate structure/activity relationships

A previous evaluation of the insulin-like activity of three 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes raised questions about structure/activity relationships, namely the influence of the hydrophilic/lipophilic balance of the complex and the capacity of the ligand to stabilize the +4 oxidation state of vanadium ion, on achieving an positive effect. To address these questions, we synthesized six new oxidovanadium(IV) complexes with variable hydrophilic/lipophilic balance, obtained by introducing different substituents on the nitrogen atom, and used two 3-hydroxy-4-pyrones as starting reagents to provide methyl and ethyl groups in the ortho position of the ring. For the new and previously reported complexes, we studied the oxidation-reduction properties and insulin-like activity in terms of inhibitory effect on Free fatty acid (FFA) release in isolated rat adipocytes. The results obtained show that only one of the complexes, Bis(3-hydroxy-1(H)-2-methyl-4-pyridonato)oxidovanadium(IV), VO(mpp)₂, exhibits a significantly greater capacity to inhibit FFA release than VOSO₄ and consequently is worthy to be considered for further studies. The establishment of structure activity relationships was not attainable but this study brings new information about the influence of some properties of the compounds on the achievement of an insulin-like effect. The results reveal that: (i) the oxidation-reduction cycles of the complexes are identical; (ii) the presence of more lipophilic substituents on the nitrogen atom does not enhance insulin-like properties; (iii) a high solubility in water proved to be not sufficient for a positive activity in inhibiting FFA release; (iv) a small molecular size may be an important property for reaching the right targets.     

Two galactomannan preparations from seeds from Mimosa scabrella (bracatinga): Complexation with oxovanadium(IV/V) and cytotoxicity on HeLa cells

Two galactomannans, GALMAN-A and GALMAN-B, were isolated from seeds of Mimosa scabrella (bracatinga), with deactivation and exposure to native enzymes, respectively. They were treated with oxovanadium(IV) and oxovanadium(V), designated (VO²⁺/VO³⁺) to form GALMAN-A:VO²⁺/VO³⁺ and GALMAN-B:VO²⁺/VO³⁺ complexes, respectively. The potentiometric studies provided the binding constants for the complexes and the resulting complexed species were a function of pH. ⁵¹V NMR spectra of GALMAN-A:VO²⁺/VO³⁺ and GALMAN-B:VO²⁺/VO³⁺ at pH 7.8 and at 30 °C indicated the occurrence of two types of complexes formed by oxovanadium ions and galactomannans. GALMAN-A:VO²⁺/VO³⁺ and GALMAN-B:VO²⁺/VO³⁺ caused loss of HeLa cells viability at concentrations of 50-200 μg/mL. GALMAN-A:VO²⁺/VO³⁺ exhibited low toxicity for 24 h, although GALMAN-B:VO²⁺/VO³⁺ was extremely toxic, since 50 μg/mL was sufficient to decrease HeLa cell viability after 48 h by 60%. GALMAN-A gave rise to a slight increase in cell proliferation after 48 h at 100 μg/mL, whereas GALMAN-B promoted a slight decrease at concentrations of 50-100 μg/mL. GALMAN-A:VO²⁺/VO³⁺ and GALMAN-B:VO²⁺/VO³⁺ exhibited a significant decrease in cell proliferation after 48 h, each reaching 60% inhibition at 5-10 μg/mL. The complexes which caused this effect were at concentrations 10 times lower than the uncomplexed polymers.     

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%).     

Interaction of VO ion with human serum transferrin and albumin

The complexation of VO²⁺ ion with the high molecular mass components of the blood serum, human serum transferrin (hTf) and albumin (HSA), has been re-examined using EPR spectroscopy. In the case of transferrin, the results confirm those previously obtained, showing that VO²⁺ ion occupies three different binding sites, A, B₁ and B₂, distinguishable in the X-band anisotropic spectrum recorded in D₂O. With albumin the results show that a dinuclear complex (VO)₂^dHSA is formed in equimolar aqueous solutions or with an excess of protein; in the presence of an excess of VO²⁺, the multinuclear complex (VO)_x^mHSA is the prevalent species, where x = 5-6 indicates the equivalents of metal ion coordinated by HSA. The structure of the dinuclear species is discussed and the donor atoms involved in the metal coordination are proposed on the basis of the measured EPR parameters. Two different binding modes of albumin can be distinguished varying the pH, with only one species being present at the physiological value. The results show that the previously named “strong” site is not the N-terminal copper binding site, and some hypothesis on the metal coordination is discussed, with the ⁵¹V A_z values for the proposed donor sets obtained by DFT (density functional theory) calculations. Finally, preliminary results obtained in the ternary system VO²⁺/hTf/HSA are shown in order to determine the different binding strength of the two proteins. Due to the low VO²⁺ concentration used, the recording of the EPR spectra through the repeated acquisition of the weak signals is essential to obtain a good signal to noise ratio in these systems.