Ligational behavior of two biologically active N-S donors toward oxovanadium(IV) ion and potentiation of their antibacterial activities by chelation to metal ions. Part III

Chelating behavior of two biologically active ligands, pyridine-2-carboxaldehyde thiosemicarbazone (PT) and pyridine-2-carboxaldehyde-(4-phenyl)thiosemicarbazone (PPT), toward oxovanadium(IV) ion has been studied. The ligands are found to react in the thioketo form (pH 2-4), yielding the complexes [VO(PT)X2](X = Cl-, Br-, ClO4-), [VO(PT)(SO4)H2O], [VO(PPT)2X]X (X = Cl-, Br-, ClO4-) and [VO(PPT)2SO4]. Reactions of [VO(PT)(SO4)H2O] and [VO(PPT)2X]X (X = Cl-, Br-, ClO4-) with a monodenate Lewis base (B) like pyridine lead to the formation of [VO(PT)(SO4)Py]H2O and [VO(PPT)2py]X2 respectively. Bonding sites of the donor molecules around the oxometal cation have been located. Nature of the EPR spectra and magnetic moment values point to the monomeric character of the complexes and suggest a distorted octahedral donor environment for the oxovanadium(IV) ion. Status of the metal-oxygen multiple bond in all the complexes has been computed in terms of the V-O(1) stretching force constant. The ligands themselves and most of their oxovanadium(IV) complexes are found to exert powerful in vitro antibacterial activities towards E. coli.     

Synthesis and insulinomimetic activities of novel mono- and tetranuclear oxovanadium(IV) complexes with 3-hydroxypyridine-2-carboxylic acid

Two chargeless VO(IV) complexes with 3-hydroxypyridine-2-carboxylic acid (H2hpic), [VO(Hhpic-O,O)(Hhpic-O,N)(H2O)].3H2O (1) and the cyclic tetramer [(VO)4(mu-(hpic-O,O',N))4(H2O)4].8H3O (2), have been synthesized and characterized by elemental analysis, mass, infrared, electronic absorption, electron spin resonance (ESR) spectroscopies, and X-ray crystallography. Their coordination structures are similar to each other (and 1 is readily transformed into 2), but are quite different from that of bis(pyridine-2-carboxylato)oxovanadium(IV). The magnetic susceptibility of 2 indicates the presence of a weak ferromagnetic intramolecular interaction between the V atoms at low temperature, in addition to a weak antiferromagnetic intermolecular interaction. The ESR signal of 2 was broad, while 1 showed an eight-line hyperfine splitting pattern due to coupling of the unpaired electron with the 51V nucleus (I=7/2). The ESR spectrum and cyclic voltammogram of 2 clearly show that the cyclic tetramer remains intact in solution. The insulinomimetic activity of 1 and 2 was evaluated by means of in vitro measurements of the inhibition of free fatty acid release from epinephrine-treated isolated rat adipocytes. While 1 exerted higher insulinomimetic activity than VOSO4, the activity of 2 was significantly lower than that of VOSO4. Hence 2 appears to retain its cyclic structure during the in vitro test. These results indicate that the rational ligand design for VO complexes might be a promising approach to obtain superior insulinomimetic activity.     

Synthesis, characterization and biological activity of oxovanadium (IV) complexes with cyclic polyalcohols

Oxovanadium (IV) complexes of the cyclic polyols conduritol C (cond) and myo-inositol (inos) of stoichiometry Na(2)[VO(cond)(2)].2H(2)O and Na(2)[VO(inos)(2)].H(2)O were obtained in aqueous alkaline solutions. They were characterized by infrared and UV-Vis spectroscopies, thermoanalytical (thermogravimetric and differential thermal analysis) data and magnetic susceptibility measurements. The biological activities of the complexes on the proliferation, differentiation and glucose consumption were tested on osteoblast-like cells in culture. Conduritol C and myo-inositol did not produce any effect on these parameters. Normal and tumoral cell proliferation was inhibited about (ca.40-60%) by the two oxovanadium (IV) complexes in concentrations as low as 100microM. The complexes were also inhibitory on cell differentiation (ca. 70-80%) while they stimulate glucose consumption. Comparisons of these effects with those of the oxovanadium (IV) cation, under the same experimental conditions, were also performed.     

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.     

Characterization of oxovanadium (IV) complexes of D-gluconic and D-saccharic acids and their bioactivity on osteoblast-like cells in culture

Oxovanadium (IV) complexes of the alpha-hydroxycarboxylic ligands D-gluconic and D-saccharic acids of stoichiometry Na(2)[VO(gluconate)(2)].H(2)O, K(2)[VO(saccharate)(2)].4H(2)O, Na(4)[VO(gluconate)(2)].2H(2)O and K(5)[VO(saccharate)(2)].4H(2)O were obtained in aqueous solutions; the first two in acid, the other two in alkaline media. They were characterized by infrared and UV-Vis spectroscopies, thermoanalytical (thermogravimetric and differential thermal analysis) data and magnetic susceptibility measurements. The complexes were found to be mononuclear, possessing the VO(2+) moiety, and the thorough analysis of the spectral data allowed the determination of the characteristics of the metal-to-ligand interactions. The biological activities of these complexes on the proliferation, differentiation and glucose consumption were tested on osteoblast-like cells in culture. Comparisons of these effects and those of the oxovanadium (IV) cation and the free ligands were performed. Different behaviors could be observed for the complexes obtained at acidic or alkaline pH-values, as well as for the different cellular types. The free ligands did not show any biological effect.     

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.     

Bis(6-ethylpicolinato)oxovanadium(IV) complex with normoglycemic activity in KK-A(y) mice.

A novel bis(6-ethylpicolinato)(H(2)O)oxovanadium(IV) complex (VO(6epa)(2) x (H(2)O)) was prepared and its structure was revealed by X-ray analysis (space group Pc(#7), a=10.838(2), b=11.148(5), c=16.642(3) A, and Z=2). Because VO(6epa)(2) x (H(2)O) exhibited higher in vitro insulinomimetic activity compared to that of vanadyl sulfate in terms of inhibition of free fatty acid (FFA) release from isolated rat adipocytes in the presence of epinephrine, its in vivo effect on whether the complex has a blood glucose normalizing effect was examined in KK-A(y) mice, a model animal of type 2 diabetes mellitus. VO(6epa)(2) x (H(2)O) was found to normalize the high blood glucose levels of KK-A(y) mice when given intraperitoneally at doses of 49 micromol/kg body weight for the first 4 days and then 39 micromol/kg body weight for 10 days. In addition, VO(6epa)(2) x (H(2)O) improved glucose tolerance ability as examined by the oral glucose test and seemed to have little toxicity in terms of serum parameters. VO(6epa)(2) x (H(2)O) showed higher normoglycemic activity than bis(6-methylpicolinato)oxovanadium(IV) (VO(6mpa)(2)) at the same dose. These results indicated that greater enhancement of the blood glucose normalizing effect in KK-A(y) mice by ethyl substitution compared to methyl substitution may be due to its being more strongly lipophilic.     

Novel vanadyl complexes with quinoxaline N(1),N(4)-dioxide derivatives as potent in vitro insulin-mimetic compounds

As a contribution to the development of novel vanadyl complexes with potential insulin-mimetic activity, three new oxovanadium(IV) complexes with the formula VO(L)(2), where L are 3-amino-quinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, have been synthesized. Complexes have been characterized by elemental and thermal analyses, fast atom bombardment mass spectroscopy (FAB-MS), conductivity measurements and electronic, Fourier transform infrared (FTIR) and electron paramagnetic resonance (EPR) spectroscopies. The in vitro insulin-mimetic activity of the vanadyl complexes has been estimated by lipolysis inhibition tests, in which the inhibition of the release of free fatty acid from isolated rat adipocytes treated with epinephrine was determined. All the complexes showed inhibitory effects on free fatty acid release. [V(IV)O(3-amino-6(7)-bromoquinoxaline-2-carbonitrile N(1),N(4)-dioxide)(2)] exhibited higher in vitro insulin-mimetic activity than the very active bis(6-methylpicolinato)oxovanadium(IV), VO(6mpa)(2). This new vanadyl complex is expected to exhibit a higher blood glucose lowering activity than VO(6mpa)(2) in diabetic animals.     

On the interaction of the vanadyl(IV) cation with lactose

A new vanadyl(IV) complex of the disaccharide lactose was obtained in aqueous solution at pH = 13. The sodium salt of the complex, of composition Na4[VO(lactose)2].3H2O, has been characterized by elemental analysis and by ultraviolet-visible, diffuse reflectance, and infrared spectroscopies. Its magnetic susceptibility and thermal behavior were also investigated. The inhibitory effect on alkaline phosphatase activity was tested for this compound as well as for the vanadyl(IV) complexes with maltose, sucrose, glucose, fructose, and galactose. For comparative purposes, the free ligands and the vanadyl(IV) cation were also studied. The free sugars and the sucrose/VO complex exhibited the lowest inhibitory effect. Lactose-VO, maltose-VO, and the free VO2+ cation showed an intermediate inhibition potential, whereas the monosaccharide/VO complexes appeared as the most potent inhibitory agents.     

Structural origins of the insulin-mimetic activity of bis(acetylacetonato)oxovanadium(IV)

We have investigated the interaction of bis(acetylacetonato)oxovanadium(IV) (VO(acac)(2)) with bovine serum albumin (BSA) by EPR and angle-selected electron nuclear double resonance, correlating results with assays of glucose uptake by 3T3-L1 adipocytes. EPR spectra of VO(acac)(2) showed no broadening in the presence of BSA; however, electron nuclear double resonance titrations of VO(acac)(2) in the presence of BSA were indicative of adduct formation of VO(acac)(2) with albumin of 1:1 stoichiometry. The influence of VO(acac)(2) on uptake of 2-deoxy-d-[1-(14)C]glucose by serum-starved 3T3-L1 adipocytes was measured in the presence and absence of BSA. Glucose uptake was stimulated 9-fold in the presence of 0.5 mm VO(acac)(2), 17-fold in the presence of 0.5 mm VO(acac)(2) plus 1 mm BSA, and 22-fold in the presence of 100 nm insulin. BSA had no influence on glucose uptake, on the action of insulin, or on glucose uptake in the presence of VOSO(4). The maximum insulin-mimetic effect of VO(acac)(2) was observed at VO(acac)(2):BSA ratios less than or equal to 1.0. Similar results were obtained also with bis(maltolato)oxovanadium(IV). These results suggest that the enhanced insulin-mimetic action of organic chelates of VO(2+) may be dependent on adduct formation with BSA and possibly other serum transport proteins.     

Platinum(II), platinum(IV), and palladium (II) complexes of amino substituted phosphine oxides: synthesis, characterization, and antitumor activity

The complexes [Pt(dapo)2Cl2], [PtNH3(dapo)Cl2], [Pt(py)(dapo)Cl2], [Pt(mbpo)Cl2].H2O, [Pt(mbpo)(OH)2Cl2].H2O, [Pd(dapo)2Cl2], and [Pd(mbpo)Cl2], where dapo is dimethyl aminomethylphosphine oxide and mbpo is methyl bis(aminomethyl)phosphite oxide have been synthesized and characterized by elemental analyses, electric conductivity, infrared, 1H NMR and electronic spectra. The ligands are found to be coordinated only via the amino groups. The complexes are of cis-square planar configuration with the exception of [Pt(mbpo)(OH)2Cl2].H2O which is pseudo-octahedral. An in vivo antitumor screening of the complexes against Leukemia L1210 was performed. A considerable activity (T/C = 233%) was observed for [PtNH3(dapo)Cl2]. The activity of the remaining complexes was below the accepted criterion.     

Synthesis, characterization and anti-diabetic effect of bis[(1-R-imidazolinyl)phenolato]oxovanadium(IV) complexes

The five-coordinate oxovanadium(IV) complexes; [VO(pimin)₂] (1a), [VO(Etpimin)₂] (2) and [VO(EtOHpimin)₂] (3), were prepared by reacting the ligands; 2-(2′-hydroxyphenyl)-1H-imidazoline (piminH), 2-(2′-hydroxyphenyl)-1-ethylimidazoline (EtpiminH) and 2-(2′-hydroxyphenyl)-1-ethanolimidazoline (EtOHpiminH), with VOSO₄. The complexes were characterized by elemental analysis, IR, UV-Vis and cyclic voltammetry. All complexes show VO stretching vibrations between 932 and 987 cm⁻¹. The presence of three d-d transition occurring between 400 and 625 nm and the irreversible oxidation (V^IV → V^V) between 400 and 490 mV confirm the d¹ electronic configuration of the complexes. The solid state structures of [VO(pimin)₂] (1a) and its autoxidation hydrolysis product [VO₂(pimin)(piminH′)] (1b) were determined by single crystal X-ray diffraction. The geometry of [VO(pimin)₂] was found to be intermediate between trigonal bipyramidal and square pyramidal and sits on a crystallographic twofold axis, while the geometry of [VO₂(pimin)(piminH′)] was distorted trigonal bipyramidal. Potentiometric titrations were used to determine the protonation and stability constants for the ligands and oxovanadium(IV) complexes, respectively. The species existing over a biological pH range were also investigated. The in vitro studies indicated that the oxovanadium(IV) complexes were effective in enhancing glucose uptake in the 3T3-L1 adipocytes, C2C12 muscle cells and Chang liver cell lines. In these cell lines, the anti-hyperglycemic effect was equivalent to or surpassed the effect of metformin.     

Synthetic analogs for oxovanadium(IV/V)-glutathione interaction: an NMR, EPR, synthetic and structural study of oxovanadium(IV/V) compounds with sulfhydryl-containing pseudopeptides and dipeptides

The reaction of [VO(CH3COO)2(phen)] (phen = 1,10-phenanthroline) with the sulfhydryl-containing pseudopeptides (scp), N-(2-mercaptopropionyl)glycine (H3mpg), N-(2-mercaptopropionyl)cysteine (H4m2pc), N-(3-mercaptopropionyl)cysteine (H4m3pc) and the dipeptides glycylglycine (H2glygly) and glycyl-L-alanine (H2glyala), in the presence of triethylamine, results in the formation of the compounds Et3NH[VO(mpg)(phen)] (1), (Et3NH)2[VO(m2pc)] (4), [(Et3NH)2[VO(m3pc) (5), [VO(glygly)(phen)] x 2CH3OH (2 x 2CH3OH) and [VO(glyala)(phen)] x CH3OH (3 x CH3OH). Evidence for the molecular connectivity in 2 x CH3OH was established by X-ray crystallography, showing the vanadium(IV) atom ligated to a tridentate glygly2- ligand at the N(amine), N(peptide) and O(carboxylato) atoms. Combination of the correlation plot of the EPR parameters gz versus Az, together with the additivity relationship supported the prediction of the equatorial donor atom sets of the V(IV)O2+ center at various pH values for the V(IV)O2+-glutathione system considered in this study. Model NMR studies (interaction of vanadium(V) with the scp H3mpg) showed that there is a possibility of vanadium(V) ligation to glutathione.     

Synthesis and spectral investigation of manganese(II), cadmium(II) and oxovanadium(IV) complexes with 2,6-diacetylpyridine bis(2-aminobenzoylhydrazone): Crystal structure of manganese(II) and cadmium(II) complexes

The chelating behavior of 2,6-diacetylpyridine bis(2-aminobenzoylhydrazone) (H₂dapa) towards manganese(II), cadmium(II) and oxovanadium(IV) ions has been studied by elemental analyses, conductance measurements, magnetic properties and spectral (IR, ¹H NMR, UV-Vis and EPR) studies. The IR spectral studies suggest the pentadentate nature of the ligand with pyridine nitrogen, two azomethine nitrogens and two carbonyl oxygen atoms as the ligating sites. Six coordinate structure for [VO(H₂dapa)]SO₄ · H₂O and seven coordinate structures for [Mn(H₂dapa)(Cl)(H₂O)]Cl · 2H₂O and [Cd(H₂dapa)Cl₂] · H₂O complexes have been proposed. Pentagonal bipyramidal geometry for [Mn(H₂dapa)(Cl)(H₂O)]Cl · 2H₂O and [Cd(H₂dapa)(Cl₂)] · H₂O complexes was confirmed by single crystal analysis. The X-band EPR spectra of the oxovanadium(IV) and manganese(II) complexes in the polycrystalline state at room (300 K) and also at liquid nitrogen temperature (77 K) were recorded and their salient features are reported.     

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.     

Metallokinetic characteristics of antidiabetic bis(allixinato)oxovanadium(IV)-related complexes in the blood of rat

The antidiabetic effect of vanadium is a widely accepted phenomenon; some oxovanadium(IV) complexes have been found to normalize high blood glucose levels in both type 1 and type 2 diabetic animals. In light of the future clinical use of these complexes, the relationship among their chemical structures, physicochemical properties, metallokinetics, and antidiabetic activities must be closely investigated. Recently, we found that among bis(3-hydroxypyronato)oxovanadium(IV) [VO(3hp)₂] related complexes, bis(allixinato)oxovanadium(IV) [VO(alx)₂] exhibits a relatively strong hypoglycemic effect in diabetic animals. Next, we examined its metallokinetics in the blood of rats that received five VO(3hp)₂-related complexes by the blood circulation monitoring–electron paramagnetic resonance method. The metallokinetic parameters were obtained from the blood clearance curves based on a two-compartment model; most parameters, such as area under the concentration curve and mean residence time, correlated significantly with the in vitro insulinomimetic activity in terms of 1/IC₅₀ (IC₅₀ is the 50% inhibitory concentration of the complex required for the release of free fatty acids in adipocytes) and the lipophilicity of the complex (log P _com). The oxovanadium(IV) concentration was significantly higher and the species resided longer in the blood of rats that received VO(alx)₂ than in the blood of rats that received VO(3hp)₂ or bis(kojato)oxovanadium(IV); VO(alx)₂ also exhibited higher log P _com and 1/IC₅₀ values. On the basis of these results, we propose that the introduction of lipophilic groups at the C2 and C6 positions of the 3hp ligand is an effective method to enhance the hypoglycemic effect of the complexes, as supported by the observed in vivo exposure and residence in the blood.     

Synthesis and antitumour activity of platinum(II) and platinum(IV) complexes containing ethylenediamine-derived ligands having alcohol, carboxylic acid and acetate substituents. Crystal and molecular structure of [PtL4CL2].H20 where L4 is ethylenediamine-N,N'-diacetate

Several cisplatin analogues of ethylenediamine-derived ligands containing alcohol, carboxylic acid and acetate substituents have been prepared and characterised. Oxidation of some of these square planar platinum(II) complexes using aqueous hydrogen peroxide gave octahedral platinum(IV) complexes, containing trans hydroxo ligands. Acetylation of the hydroxo ligands was achieved by reaction with acetic anhydride, giving complexes which are analogues of the antitumour drug, JM-216. Oxidation of the complex [Pt(H2L4)Cl2], where H2L4 is ethylenediamine-N,N'-diacetic acid, with H2O2 gave the platinum(IV) complex [PtL4Cl2].H2O in which L4 is tetradentate as shown by a crystal and molecular structure. This complex was previously reported to be [Pt(HL4)(OH)Cl2] in which HL4 is tridentate. Several of the complexes were tested for antitumour activity against five human ovarian carcinoma cell lines. IC50 values range from 4.0 microM for cis,trans-PtCl2(OH)2(NH2CH2CH2NHCH2CH2OH) against the CH1 cell line to >25 microM indicating moderate to low activity relative to other platinum complexes.     

Polynuclear diorganotin(IV) complexes with arylhydroxamates: Syntheses, structures and in vitro cytotoxic activities

Series of polynuclear diorganotin(IV) complexes with di-halogenbenzohydroxamate ligands (substituents=2,4-Cl(2), 2,4-F(2), 3,4-F(2), 2,5-F(2), 2,6-F(2)), formulated as the polymeric [R(2)SnL](n)a (1:1) and the tetranuclear [R(4)Sn(2)(HL)(2)(L)](2)b (2:3) (HL=arylhydroxamate), were prepared and characterized by FT-IR, (1)H, (13)C, (119)Sn NMR spectroscopies, elemental analyses and melting point measurements. X-ray diffraction analyses were also carried out for the representative complexes [Me(2)Sn{2,4- F(2)C(6)H(3)C(O)NO}](n)2a and [n-Bu(4)Sn(2){2,4- F(2)C(6)H(3)C(O)NHO}(2) {2,4-F(2)C(6)H(3)C(O)NO}] (2)1b and show that the ligated mono- and di-basic forms, HL and L, of the arylhydroxamic acid (H(2)L) display the oxamic and oximic tautomeric forms, respectively. These compounds exhibit in vitro cytotoxicities toward human leukemic promyelocites HL-60, BGC-823, BEL-7402 and KB cell lines which, in some cases, are identical to, or even higher than, that of "cisplatin". The polymeric diorganotin/hydroxamato complexes a containing the long carbon chain butyl ligands are the most active ones, and the dependence of the antitumor activity of the complexes on various factors, namely the nuclearity, the organic ligand, the type, position and number of the X ring substituents, is also discussed.     

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).     

Reduction of vanadium(V) with ascorbic acid and isolation of the generated oxovanadium(IV) species

The interaction of sodium metavanadate and VOCl₃ with ascorbic acid, one of the possible natural reducing agents of vanadium(V) to oxovanadium(IV), has been investigated. Three new VO²⁺ complexes could be isolated as microcrystalline powders. One of them, of composition K_1.5Na_0.5[VO(HAsc)(OH)₃], contains ascorbic acid as a monodentate ligand. In the other two, K[VO(Diketo)(OH)]·H₂O and Na₃[VO(Diketo)₂(OH)], the enolized form of 2,3-diketogulonic acid (one of the oxidation products of ascorbic acid), acts as a bidentate ligand. The complexes were characterized by means of electronic (absorption and reflectance) and infrared spectroscopy and magnetic susceptibility measurements. Their thermal behavior was investigated by thermogravimetric and differential thermal analyses. The interest of the investigated system in relation to vanadium detoxification is also discussed.