An in vitro study of interactions between insulin-mimetic zinc(II) complexes and selected plasma components

The speciations of some potent insulin-mimetic zinc(II) complexes of bidentate ligands: maltol and 1,2-dimethyl-3-hydroxypyridinone with (O,O) and picolinic acid with (N,O) coordination modes, were studied via solution equilibrium investigations of the ternary complex formation in the presence of small relevant bioligands of the blood serum such as cysteine, histidine and citric acid. Results show that formation of the ternary complexes, especially with cysteine, is favoured at physiological pH range in almost all systems studied. Besides these low molecular mass binders, serum proteins among others albumin and transferrin can bind zinc(II) or its complexes. Accordingly, the distribution of zinc(II) between the small and high molecular mass fractions of the serum was also studied by ultrafiltration. Modelling calculations relating to the distribution of zinc(II), using the stability constants of the ternary complexes studied and those of the serum proteins reported in the literature, confirmed the ultrafiltration results, namely, the primary role of albumin in zinc(II) binding among the low and high molecular mass components of the serum.     

Speciation of insulin-mimetic VO(IV)-containing drugs in blood serum

The biospeciations of three potential insulin-mimetic VO(IV) compounds, VO(maltolate)2, VO(picolinate)2 and VO(6-Me-picolinate)2, in blood serum were assessed via modelling calculations, using the stability constants reported in the literature for the binary insulin-mimetic complexes and their ternary complexes formed with the most important low molecular mass binders in the serum: oxalic acid, lactic acid, citric acid and phosphate. The binding capabilities of two high molecular mass serum proteins, albumin and transferrin, were also taken into account.     

Computer simulation of Zn(II) speciation and effect of Gd(III) on Zn(II) speciation in human blood plasma

The speciation and distribution of Zn(II) and the effect of Gd(III) on Zn(II) speciation in human blood plasma were studied by computer simulation. The results show that, in normal blood plasma, the most predominant species of Zn(II) are [Zn(HSA)] (58.2%), [Zn(IgG)](20.1%), [Zn(Tf)] (10.4%), ternary complexes of [Zn(Cit)(Cys)] (6.6%) and of [Zn(Cys)(His)H] (1.6%), and the binary complex of [Zn(Cys)₂H] (1.2%). When zinc is deficient, the distribution of Zn(II) species is similar to that in normal blood plasma. Then, the distribution changes with increasing zinc(II) total concentration. Overloading Zn(II) is initially mainly bound to human serum albumin (HSA). As the available amount of HSA is exceeded, phosphate metal and carbonate metal species are established. Gd(III) entering human blood plasma predominantly competes for phosphate and carbonate to form precipitate species. However, Zn(II) complexes with phosphate and carbonate are negligible in normal blood plasma, so Gd(III) only have a little effect on zinc(II) species in human blood plasma at a concentration above 1.0×10⁻⁴ M.     

Metal based drugs: design,synthesis and in-vitro antimicrobial screening of Co(II), Ni(II), Cu(II) and Zn(II) complexes with some new carboxamide derived compounds: crystal structures of N-[ethyl(propan-2-yl)carbamothioyl]thiophene-2-carboxamide and its copper(II) complex

A new series of compounds derived from thiophene-2-carboxamide were synthesized and characterized by IR, ¹H-NMR and ¹³C-NMR, mass spectrometry and elemental analysis. These compounds were further used to prepare their Co(II), Ni(II), Cu(II) and Zn(II) metal complexes. All metal(II) complexes were air and moisture stable. Physical, spectral and analytical data have shown the Ni(II) and Cu(II) complexes to exhibit distorted square-planar and Co(II) and Zn(II) complexes tetrahedral geometries. The ligand (L¹) and its Cu(II) complex were characterized by the single-crystal X-ray diffraction method. All the ligands and their metal(II) complexes were screened for their in-vitro antimicrobial activity. The antibacterial and antifungal bioactivity data showed that the metal(II) complexes were found to be more potent than the parent ligands against one or more bacterial and fungal strains.     

Zn(II) and Hg(II) complexes of naphthalene based thiosemicarbazone: Structure and spectroscopic studies

Synthesis, structure and spectroscopic characterization of 2-thiophenealdehyde-N(4)-napthylthiosemicarbazone and its complexes with biologically important Zn(II) and toxic Hg(II) metal ions have been reported. The crystal structure of the complexes reveals that both are distorted tetrahedral. In the Hg(II) complex the ligand is neutral and mondented where as in Zn(II) complex the ligand is bidented and anionic. Whereas conductivity measurement study shows both the complexes are molecular species. The beautiful changes in absorption spectra along with isosbestic points upon addition of respective metal salts to the ligand solution convincingly support the formation of metal complexes in solution phase. The other spectroscopic studies also show good correlation with their solid state structures.     

Human fetal endothelial cells acquire Zinc(II) from both the protein bound and nonprotein bound pools in serum

To help determine physiologically important routes by which zinc (Zn) is acquired by human fetal vascular endothelium, the authors incubated cultured umbilical vein endothelial cells with⁶⁵Zn(II)-tracer labeled human fetal whole serum, ultrafiltrate (containing low molecular mass serum zinc complexes), and dialyzed serum (containing protein-bound zinc). Zinc from whole serum and from both serum fractions entered a rapidly labeled cellular compartment removable by edetic acid (EDTA), representing Zn bound to the outside cell surface, and accumulatively, an EDTA-resistant compartment’probably largely internalized Zn. Entry of Zn into the EDTA-resistant pool from both serum fractions was strongly temperature-dependent, and was not via the EDTA-sensitive pool. Entry from the ultrafiltrate was resolvable into high affinity saturable, and non-(or hardly-) saturable components. Transfer from the dialyzed serum fraction was not significantly saturable, but only partially accounted for by nonspecific pinocytosis. Thus, Zn is obtained by fetal vascular endothelium partly from low molecular mass serum species, probably through at least one carrier-mediated membrane transport system; but also from Zn complexed with serum protein, via at least one metabolism-related route.     

Electron transfer. Part 165: Oxidations of Ti(II)(aq) with ligated iron(III) and ruthenium(III)

Titanium(II) solutions, prepared by dissolving titanium wire in triflic acid + HF, contain equimolar quantities of Ti(IV). Treatment of such solutions with excess Fe(III) or Ru(III) complexes yield Ti(IV), but reactions with Ti(II) in excess give Ti(III). Oxidations by (NH₃)₅Ru(III) complexes, but not by Fe(III) species, are catalyzed by titanium(IV) and by fluoride. Stoichiometry is unchanged. The observed rate law for the Ru(III)-Ti(II)-Ti(IV) reactions in fluoride media points to competing reaction paths differing by a single F⁻, with both routes involving a Ti(II)-Ti(IV) complex which is activated by deprotonation. It is suggested that coordination of Ti(IV) to Ti^II(aq) minimizes the mismatch of Jahn-Teller distortions which would be expected to lower the Ti(II,III) self-exchange rate.     

Cleavage of an RNA analog by Zn(II) macrocyclic catalysts appended with a methyl or an acridine group

Two macrocycles (1 and 2) are prepared that incorporate pendent groups in macrocycle 3 (3=1-oxa-4,7,10-triazacyclododecane) with the goal of studying the effect of these pendent groups on metal ion complexation, solution chemistry and catalysis. Zn(1) contains a macrocyclic ligand with a pendent acridine group and Zn(2) has an appended methyl group. Water ligand pK(a) values for Zn(1) (6.7) and Zn(2) (7.3) are lower than that of Zn(3) (7.7). Zn(II) complexes of 1 and 2 are studied as catalysts for the cleavage of 2-hydroxypropyl 4-nitrophenylphosphate (HpPNP), an RNA analog. Zn(2) has a lower catalytic activity over the pH range 7-10 for cleavage of HpPNP compared to the parent macrocyclic complex, Zn(3). In contrast, Zn(1) has a threefold larger rate constant at pH 7.0 compared to Zn(2), attributed to the presence of a catalytic species which has a protonated acridine amino group. The binding constant of 1.5mM at pH 8.0 for formation of the Zn(2)-uridine adduct is similar to that for Zn(3), suggesting that N-alkylation of the macrocyclic ligand does not interfere with binding of the Zn(II) complex to uridine groups. Binding of cytidine to Zn(2) was not detectable under similar conditions up to 25mM nucleoside. Binding experiments under similar conditions could not be carried out for adenosine or guanosine due to their low solubility.     

Synthesis,physico-chemical characterization and antimicrobial activity of cobalt(II), nickel(II), copper(II), zinc(II) and cadmium(II) complexes with some acyldihydrazones

Complexes of the type [M(bssdh)]Cl and [M(dspdh)]Cl, where M = Co(II), Ni(II), Cu(II), Zn(II) and Cd(II); Hbssdh = benzil salicylaldehyde succinic acid dihydrazone, Hdspdh = diacetyl salicylaldehyde phthalic acid dihydrazone have been synthesized and characterized with the help of elemental analyses, electrical conductance, magnetic susceptibility measurements, electronic, ESR and IR spectra and X–ray diffraction studies. Magnetic moment values and electronic spectral transitions indicate a spin free octahedral structure for Co(II), Ni(II) and Cu(II) complexes. IR spectral studies suggest that both the ligands behave as monobasic hexadentate ligands coordinating through three > C = O, two > C = N– and a phenolate group to the metal. ESR spectra of Cu(II) complexes are axial type and suggest as the ground state. X–ray powder diffraction parameters for [Co(bssdh)]Cl and [Co(dspdh)]Cl complexes correspond to an orthorhombic crystal lattice. The ligands as well as their metal complexes show a significant antifungal and antibacterial activity against various fungi and bacteria. The metal complexes are more active than the parent ligands.     

Electroporation Enhances the Anticancer Effects of Novel Cu(II) and Fe(II) Complexes in Chemotherapy-Resistant Glioblastoma Cancer Cells

Schiff base ligand (L) was obtained by condensation reaction between 4-aminopyrimidin-2(1H)-one (cytosine) with 2-hydroxybenzaldehyde. The synthesized Schiff base was used for complexation with Cu(II) and Fe(II) ions used by a molar (2 : 1 mmol ration) in methanol solvent. The structural features of ligand, Cu(II), and Fe(II) metal complexes were determined by standard spectroscopic methods (FT-IR, elemental analysis, proton and carbon NMR spectra, UV/VIS, and mass spectroscopy, magnetic susceptibility, thermal analysis, and powder X-ray diffraction). The synthesized compounds (Schiff base and its metal complexes) were screened in terms of their anti-proliferative activities in U118 and T98G human glioblastoma cell lines alone or in combination with electroporation (EP). Moreover, the human HDF (human dermal fibroblast) cell lines was used to check the bio-compatibility of the compounds. Anti-proliferative activities of all compounds were ascertained using an MTT assay. The complexes exhibited a good anti-proliferative effect on U118 and T98G glioblastoma cell lines. In addition, these compounds had a negligible cytotoxic effect on the fibroblast HDF cell lines. The use of compounds in combination with EP significantly decreased the IC₅₀ values compared to the use of compounds alone (p<0.05). These results show that newly synthesized Cu(II) and Fe(II) complexes can be developed for use in the treatment of chemotherapy-resistant U118 and T98G glioblastoma cells and that treatment with lower doses can be provided when used in combination with EP.     

Solution equilibrium characterization of insulin-mimetic Zn(II) complexes

Solution speciation (stoichiometry and stability constants) of the insulin mimetic Zn(II) complexes of several bidentate ligands with (O,O), (N,O) or (S,O) coordination modes have been determined by pH-metry at 25 degrees Celsius and I=0.2M (KCl). All ligands were found to coordinate in a bidentate way forming mono, bis and tris complexes, besides a mixed hydroxo bis complex ZnL(2)(OH) detected in the slightly basic pH range together with the tris complex. Relationships between the stability data, lipophilicity of the complexes and earlier biological data are evaluated. The validity of the linear free energy relationships (LFER) between the proton and Zn(II) complexes and also between the VO(IV) and Zn(II) complexes is tested.     

A new type of orally active anti-diabetic Zn(II)-dithiocarbamate complex

In order to find orally active Zn(II) complexes that can treat diabetes mellitus (DM) at low doses, four new Zn(II)-dithiocarbamate complexes with Zn(II)-sulfur coordination bonds were prepared and their in vitro insulinomimetic activity and in vivo anti-diabetic ability were evaluated. Among the Zn(II)-dithiocarbamate complexes, the bis(pyrrolidine-N-dithiocarbamate)zinc(II) (Zn(pdc)(2)) complex was found to be the most effective in terms of inhibiting free fatty acid-release and enhancing glucose-uptake in adipocytes. After oral administration of the Zn(pdc)(2) complex to KK-A(y) mice with obesity and type 2 DM, we observed that the high blood glucose levels in the mice were lowered from approximately 500 mg/dL to 350 mg/dL within 6 days, and the effect was maintained during the administration period. Also, indicators of insulin resistance such as serum insulin, leptin, and triglyceride levels were also reduced compared with those in untreated mice. Moreover, the Zn(pdc)(2) complex improved not only the hypertension in the mice, but also the adiponectin level in the serum. On the basis of the results, the Zn(pdc)(2) complex is proposed to improve hyperglycemia and insulin resistance in type 2 DM animals on daily oral administrations.     

Novel palladium(II) and Zinc(II) Schiff base complexes: Synthesis,biophysical studies,and anticancer activity investigation

BackgroundSchiff base metal complexes are considered promising chemotherapeutic agents due to their potential application in cancer therapy.MethodsThe current work sought to synthesize a brand-new Schiff base ligand obtained from 2-hydroxybenzohydrazide and (E)− 1-(2-(p-tolyl)hydrazono)propan-2-one with metal ions which included Pd(II) and Zn(II) ions. Elemental analyses, FT-IR, mass spectra, 1H NMR, UV-Vis spectrometer, and computational analysis characterized the compound's structure. In vitro, the breast cancer cell line (MCF-7) was tested for its sensitivity to Schiff base (HL) and its Pd(II) and Zn(II) complexes. The half-maximal inhibitory concentration IC₅₀ of the compounds was determined and used to perform the comet assay, which was carried out to reveal the photo-induced DNA damaging ability of the compounds of individual cells. Moreover, the compounds' effects on antioxidant defense systems of enzymes in cells: superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and oxidant Malondialdehyde (MDA) were examined in MCF-7 cells.ResultsThe Pd(II) complex displayed approximately the same IC₅₀ as Cisplatin, while Zn(II) complex had better activity than Cisplatin with very low IC₅₀, 1.40 μg/ml. Significant alterations in SOD, CAT, GPx, and MDA production were discovered, inducing oxidative stress, enlarging ROS production, and reducing the antioxidant amount. This change was approximately similar in most compounds. Consequently, it promoted apoptosis, particularly the Zn(II) complex, which demonstrated an improved impact because of its ability to influence the antioxidant defense systems of enzymes, mostly SOD and GPx, besides increasing MDA levels.ConclusionIt can be concluded that Zn(II) complex is the most effective anticancer drug since it induced a very similar genotoxic effect as Cisplatin and has a very low IC₅₀ value.     

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, structure and characterization of novel Cd(II) and Zn(II) complexes with the condensation product of 2-formylpyridine and selenosemicarbazide: Antiproliferative activity of the synthesized complexes and related selenosemicarbazone complexes

Two novel Cd(II) and Zn(II) complexes with the condensation product of 2-formylpyridine and selenosemicarbazide were synthesized. The structure of Cd(II) complex was determined by X-ray crystallography. The ligand is coordinated in a neutral form via pyridine and azomethine nitrogen atoms and the selenium donor. The cadmium ion completes its five-coordination by two chloride ligands, forming a square-pyramidal geometry. The structure of Zn(II) complex was established by analysis of spectroscopic data, which indicated coordination of the ligand as a bidentate via the selenium and the azomethine nitrogen atoms. The cytotoxic activity of the newly synthesized complexes, as well as if five structurally related complexes and the ligand evaluated against eight tumor cell lines. The new Cd(II) complex showed the highest activity similar to cisplatin with IC50 less than 10 μM for all cell lines. Cell cycle distribution and apoptosis study showed that Cd(II) complex and cisplatin might have some similarity in anticancer activity, which was not the case for cisplatin and other studied complexes. Effects of the complexes on matrix metalloproteinases (MMPs) MMP-9 and MMP-2 was also studied. Cd(II) and Zn(II) complexes and cisplatin increased MMP-2 activity in supernatants of tested cells, while Ni(II) complex with the same ligand decreased the activity, implying a possible activity in preventing tumor invasion and metastasis processes.     

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 chemical characterization of Cu, Ni and Zn complexes of 3,5-bis(2′-pyridyl)-1,2,4-oxadiazole and 3-(2′-pyridyl)5-(phenyl)-1,2,4-oxadiazole ligands

The synthesis and structural characterization of Ni^II, Cu^II and Zn^II complexes of two chelating 1,2,4-oxadiazole ligands, namely 3,5-bis(2′-pyridyl)-1,2,4-oxadiazole (bipyOXA) and 3-(2′-pyridyl)5-(phenyl)-1,2,4-oxadiazole (pyOXA), is here reported. The formed hexacoordinated metal complexes are [M(bipyOXA)₂(H₂O)₂](ClO₄)₂ and [M(pyOXA)₂(ClO₄)₂], respectively (M = Ni, Cu, Zn). X-ray crystallography, ¹H and ¹³C NMR spectroscopy and C, N, H elemental analysis data concord in attributing them an octahedral coordination geometry. The two coordinated pyOXA ligands assume a trans coplanar disposition, while the two bipyOXA ligands are not. The latter result is a possible consequence of the formation of H-bonds between the coordinated water molecules and the nitrogen atom of the pyridine in position 5 of the oxadiazole ring. The expected splitting of the d metal orbitals in an octahedral ligand field explains the observed paramagnetism of the d⁸ and d⁹ electron configuration of the nickel(II) and copper(II) complexes, respectively, as determined by the broadening of their NMR spectra.     

Enantiomeric Specificity of Biologically Significant Cu(II) and Zn(II) Chromone Complexes Towards DNA

Novel chiral Schiff base ligands (R)/(S)‐2‐amino‐3‐(((1‐hydroxypropan‐2‐yl)imino)methyl)‐4H‐chromen‐4‐one (L₁ and L₂) derived from 2‐amino‐3‐formylchromone and (R/S)‐2‐amino‐1‐propanol and their Cu(II)/Zn(II) complexes ( R1 , S1 , R2 , and S2 ) were synthesized. The complexes were characterized by elemental analysis, infrared (IR), hydrogen (¹H) and carbon (¹³C) nuclear magnetic resonance (NMR), electrospray ionization‐mass spectra (ESI‐MS), and molar conductance measurements. The DNA binding studies of the complexes with calf thymus were carried out by employing different biophysical methods and molecular docking studies that revealed that complexes R1 and S1 prefers the guanine–cytosine‐rich region, whereas R2 and S2 prefers the adenine–thymine residues in the major groove of DNA. The relative trend in K_b values followed the order R1 S1 R2 S2 . This observation together with the findings of circular dichroic and fluorescence studies revealed maximal potential of (R)‐enantiomeric form of complexes to bind DNA. Furthermore, the absorption studies with mononucleotides were also monitored to examine the base‐specific interactions of the complexes that revealed a higher propensity of Cu(II) complexes for guanosine‐5′‐monophosphate disodium salt, whereas Zn(II) complexes preferentially bind to thymidine‐5′‐monophosphate disodium salt. The cleavage activity of R1 and R2 with pBR322 plasmid DNA was examined by gel electrophoresis that revealed that they are good DNA cleavage agents; nevertheless, R1 proved to show better DNA cleavage ability. Topoisomerase II inhibitory activity of complex R1 revealed that the complex inhibits topoisomerase II catalytic activity at a very low concentration (25 μM). Furthermore, in vitro antitumor activity of complexes R1 and S1 were screened against human carcinoma cell lines of different histological origin. Chirality 24:977–986, 2012. © 2012 Wiley Periodicals, Inc.     

Synthesis and characterization of four novel palladium(II) and platinum(II) complexes with 1‐(2‐aminoethyl)pyrrolidine,diclofenac and mefenamic acid: In vitro effect of these complexes on human serum paraoxanase1 activity

In this study, the effects of four novel mononuclear palladium(II) and platinum(II) complexes on the activity of human serum paraoxanase1 were examined. First, four novel mononuclear palladium(II) and platinum(II) complexes were synthesized with a nitrogen donor ligand 1‐(2‐aminoethyl)pyrrolidine and nonsteroidal anti‐inflammatory drugs diclofenac, mefenamic acid. These complexes were characterized by spectroscopic, thermal, and elemental analyses. The crystal structures of complex [Pd(2‐amepyr)₂](dicl)₂ 1 and [Pd(2‐amepyr)₂](mef)₂ 3 were determined by X‐ray crystallography. Then, paraoxonase1 enzyme was purified from human serum. The effects of these complexes on enzyme were evaluated in vitro. The complexes consist of the cationic unit and the counterions. The diclofenac and mefenamic acid acted as a counterion in the complexes. It was observed that all the complexes were stable up to high temperatures. These complexes, even at low doses, inhibited the activity of the enzyme with different inhibition mechanisms.