A new insulin-mimetic bis(allixinato)zinc(II) complex: structure–activity relationship of zinc(II) complexes

During the investigation of the development of insulin-mimetic zinc(II) complexes with a blood glucose-lowering effect in experimental diabetic animals, we found a potent bis(maltolato)zinc(II) complex, Zn(ma)₂, exhibiting significant insulin-mimetic effects in a type 2 diabetic animal model. By using this Zn(ma)₂ as the leading compound, we examined the in vitro and in vivo structure–activity relationships of Zn(ma)₂ and its related complexes. The in vitro insulin-mimetic activity of these complexes was determined by the inhibition of free fatty acid release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine. A new Zn(II) complex with allixin isolated from garlic, Zn(alx)₂, exhibited the highest insulin-mimetic activity among the complexes analyzed. The insulin-mimetic activity of the Zn(II) complexes examined strongly correlated (correlation coefficient=0.96) with the partition coefficient (logP) of the ligand, indicating that the activity of Zn(ma)₂-related complexes depends on the lipophilicity of the ligand. The blood glucose-lowering effects of Zn(alx)₂ and Zn(ma)₂ were then compared, and both complexes were found to normalize hyperglycemia in KK-A^y mice after a 14-day course of daily intraperitoneal injections. However, Zn(alx)₂ improved glucose tolerance in KK-A^y mice much more than did Zn(ma)₂, indicating that Zn(alx)₂ possesses greater in vivo anti-diabetic activity than Zn(ma)₂. In addition, Zn(alx)₂ improved leptin resistance and suppressed the progress of obesity in type 2 diabetic KK-A^y mice. On the basis of these observations, we conclude that the Zn(alx)₂ complex is a novel potent candidate for the treatment of type 2 diabetes mellitus.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00775-004-0590-8     

Development of new insulinomimetic zinc(II) picolinate complexes with a Zn(N2O2) coordination mode: structure characterization, in vitro, and in vivo studies

Three zinc(II) complexes of picolinic acid and its derivatives with a Zn(N2O2) coordination mode were prepared and evaluated for their insulinomimetic activities by in vitro and in vivo studies. By introducing an electron-donating methyl group into the picolinate ligand (pic), bis(6- or 3-methylpicolinato)zinc(II) complexes [Zn(6-mpa)2 or Zn(3-mpa)2, respectively] were prepared. The Zn(6-mpa)(2) complex was crystallized as a water adduct [Zn(6-mpa)2(H2O)].H2O, in which two carboxylate oxygens and two pyridine nitrogens of 6-mpa and a water oxygen coordinate to a zinc(II) with a trigonal bipyramidal geometry. By in vitro evaluation of the inhibition of free fatty acid (FFA) release from isolated rat adipocytes in the presence of epinephrine, the insulinomimetic activities of Zn(pic)2, Zn(6-mpa)2, and Zn(3-mpa)2 (IC50=0.64 +/- 0.13, 0.31 +/- 0.05, and 0.40 +/- 0.07 mM, respectively) were found to be higher than those of VOSO(4) (IC50=1.00 mM) and ZnSO(4) (IC50=1.58 +/- 0.05 mM) in terms of IC50 value, the 50% inhibition concentrations for the FFA release from the adipocytes. Then, Zn(6-mpa)2, which exhibited the highest in vitro insulinomimetic activity among three complexes examined, was given at a dose of 3.0 mg (45.9 micromol) Zn/kg body weight to KK-A(y) mice with type 2 diabetes mellitus by daily intraperitoneal injections for 14 days and it was found that the hereditary high blood glucose levels were lowered during the administration of the complex. The improvement of diabetes mellitus was confirmed with the oral glucose tolerance test.     

Synthesis,structural characterization and antimicrobial activities of 12 zinc(II) complexes with four thiosemicarbazone and two semicarbazone ligands

Twelve zinc(II) complexes with thiosemicarbazone and semicarbazone ligands were prepared and characterized by elemental analysis, thermogravimetric and differential thermal analysis (TG/DTA), FT-IR and 1H and 13C NMR spectroscopy. Seven three-dimensional structures of zinc(II) complexes were determined by single-crystal X-ray analysis. Their antimicrobial activities were evaluated by MIC against four bacteria (B. subtilis, S. aureus, E. coli and P. aeruginosa), two yeasts (C. albicans and S. cerevisiae) and two molds (A. niger and P. citrinum). The 5- and 6-coordinate zinc(II) complexes with a tridentate thiosemicarbazone ligand (Hatsc), ([Zn(atsc)(OAc)](n) 1, [Zn(Hatsc)(2)](NO(3))(2).0.3H(2)O 2, [ZnCl(2)(Hatsc)] 3 and [Zn(SO(4))(Hatsc)(H(2)O)].H(2)O 4 [Hatsc=2-acetylpyridine(thiosemicarbazone)]), showed antimicrobial activities against test organisms, which were different from those of free ligands or the starting zinc(II) compounds. Especially, complex 2 showed effective activities against P. aeruginosa, C. albicans and moderate activities against S. cerevisiae and two molds. These facts are in contrast to the results that the 5- or 6-coordinate zinc(II) complexes with a tridentate 2-acetylpyridine-4N-morpholinethiosemicarbazone, ([Zn(mtsc)(2)].0.2EtOH 5, the previously reported catena-poly [Zn(mtsc)-mu-(OAc-O,O')](n) and [Zn(NO(3))(2)(Hmtsc)] [Hmtsc=2-acetylpyridine (4N-morpholyl thiosemicarbazone)]), showed no activities against the test microorganisms. The 5- and 6-coordinate zinc(II) complexes with a tridentate 2-acetylpyridinesemicarbazone, ([Zn(OAc)(2)(Hasc)] 6 and [Zn(Hasc)(2)](NO(3))(2) 7 [Hasc=2-acetylpyridine(semicarbazone)]), showed no antimicrobial activities against bacteria, yeasts and molds. Complex [ZnCl(2)(Hasc)] 8, which was isostructural to complex 3, showed modest activity against Gram-positive bacterium, B. subtilis. The 1:1 complexes of zinc(II) with pentadentate thiosemicarbazone ligands, ([Zn(dmtsc)](n) 9 and [Zn(datsc)](n) 10 [H(2)dmtsc=2,6-diacetylpyridine bis(4N-morpholyl thiosemicarbazone) and H(2)datsc=2,6-diacetylpyridine bis(thiosemicarbazone)]), did not inhibit the growth of the test organisms. On the contrary, 7-coordinate zinc(II) complexes with one pentadentate semicarbazone ligand and two water molecules, ([Zn(H(2)dasc)(H(2)O)(2)](OAc)(2).5.3H(2)O 11 and [Zn(H(2)dasc)(H(2)O)(2)](NO(3))(2).H(2)O 12 [H(2)dasc=2,6-diacetylpyridine bis(semicarbazone)]), showed modest to moderate activities against bacteria. Based on the X-ray structures, the structure-activity correlation for the antimicrobial activities was elucidated. The zinc(II) complexes with 4N-substituted ligands showed no antimicrobial activities. In contrast to the previously reported nickel(II) complexes, properties of the ligands such as the ability to form hydrogen bonding with a counter anion or hydrated water molecules or the less bulkiness of the 4N moiety would be a more important factor for antimicrobial activities than the coordination number of the metal ion for the zinc(II) complexes.     

Syntheses of vanadyl and zinc(II) complexes of 1-hydroxy-4,5,6-substituted 2(1H)-pyrimidinones and their insulin-mimetic activities

Control of the glucose level in the blood plasma has been achieved in vitro and in vivo by administration of vanadium and zinc in form of inorganic salts. It has been shown that elements are poorly absorbed in their inorganic forms and required high doses which have been associated with undesirable side effects. Many researchers, therefore, have focused on metal complexes that were prepared from VOSO(4) or ZnSO(4) and low-molecular-weight bidentate ligands. Seven kinds of 1-hydroxy-4,6-disubstituted and 1-hydroxy-4,5,6-trisubstituted-2(1H)-pyrimidinones were synthesized by reaction of N-benzyloxyurea and beta-diketones and subsequent removal of the protecting group. Six kinds of 1-hydroxy-4-(substituted)amino-2(1H)-pyrimidinones were synthesized by the substitution reaction of 1-benzyloxy-4-(1',2',4'-triazol-1'-yl)-2(1H)-pyrimidinone with various alkyl amines or amino acids. Treatment with VOSO(4) and ZnSO(4) or Zn(OAc)(2) afforded vanadyl(IV) and zinc(II) complexes which were characterized by means of (1)H NMR, IR, EPR, and UV-vis spectroscopies, and combustion analysis. The in vitro insulin-mimetic activity of these complexes was evaluated from 50% inhibitory concentrations (IC(50)) on free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. Vanadyl complexes of 4,6-disubstituted-2(1H)-pyrimidinones showed higher insulin-mimetic activities than those of 4,5,6-trisubstituted ones. On the other hand, Zn(II) complexes showed lower insulin-mimetic activities than VOSO(4) and ZnSO(4) as positive controls. It was found that the balance of the hydrophilicity and/or hydrophobicity is important for higher insulin-mimetic activity. The in vivo insulin-mimetic activity was evaluated with streptozotocin (STZ)-induced diabetic rats. Blood glucose levels were lowered from hyperglycemic to normal levels after the treatment with bis(1,2-dihydro-4,6-dimethyl-2-oxo-1-pyrimidinolato)oxovanadium(IV) by daily intraperitoneal injections. The improvement in glucose tolerance was also confirmed by an oral glucose tolerance test.     

The preparation and crystal structure of acetatobis(l-arginine)zinc(II) acetate trihydrate, the first reported X-ray structure of a zinc(II)-arginine complex

The synthesis and X-ray crystal structure of acetatobis(l-arginine)zinc(II) acetate trihydrate, [Zn(OAc)(l-Arg)₂]OAc·3H₂O is reported. In this structure, the first of a zinc(II)-arginine complex to be reported, the geometry around zinc(II) is distorted square-pyramidal containing two trans-N,O chelated l-Arg ligands in the basal plane and the acetato ligand in an axial position. The structure contains a second acetate which is salt-bridged to the δ and ω NH groups of the guanidinium side chain of an arginine ligand and also contains three hydrogen bonded water molecules.     

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.     

Synthesis, structural characterization, antiradical and antidiabetic activities of copper(II) and zinc(II) Schiff base complexes derived from salicylaldehyde and beta-alanine

A series of copper(II) and zinc(II) complexes involving a tridentate O,N,O'-donor Schiff base derived from salicylaldehyde and beta-alanine {i.e. N-salicylidene-beta-alanine(2-), (L)}, having the composition [Cu(2)(L)(2)(H(2)O)].H(2)O (1), [Cu(L)(H(2)O)](n) (2), and [Zn(L)(H(2)O)](n) (3), have been prepared and characterized by elemental analyses, UV-visible (UV-VIS), FT-IR and ESI-MS spectra, and thermal analyses. Complexes 1 and 2 have been investigated by single crystal X-ray analysis and also by temperature dependent magnetic susceptibility measurements (294-80K). All prepared complexes have been evaluated by the antiperoxynitrite activity assay and alloxan-induced diabetes model. The significant antioxidant and antidiabetic activities have been found in the case of both copper(II) complexes 1 and 2. In spite of first two complexes, the zinc(II) complex 3, as well as the potassium salt of the ligand (KHL) showed only insignificant protective effect against the tyrosine nitration in vitro.     

Insulinomimetic bis(maltolato)zinc(II) complex: blood glucose normalizing effect in KK-A(y) mice with type 2 diabetes mellitus

High blood glucose levels of KK-A(y) mice with type 2 diabetes mellitus were normalized by daily intraperitoneal (ip) administration of a zinc(II) complex, bis(maltolato)zinc(II) (Zn(Mal)(2)) with a Zn(O(4)) coordination mode, following the finding of strong in vitro insulinomimetic activity in isolated rat adipocytes treated with epinephrine in terms of the inhibition of free fatty acid release. The blood glucose level was maintained in the normal range during administration of the Zn(Mal)(2) complex for 14 days and improvements in the glucose tolerance were confirmed by an oral glucose tolerance test.     

EXAFS studies of the zinc sites of UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC)

Extended X-ray absorption fine structure (EXAFS) spectroscopy has been used to determine the structure of the Zn(II) sites in UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC) from Aquifex aeolicus and Pseudomonas aeruginosa. The active site Zn(II) is four coordinate, with exclusively low-Z (nitrogen and oxygen) ligation in both enzymes. The amplitude of the outer-shell scattering from the histidine ligands is best fit using two histidine ligands, suggesting a ZnO(2)(His)(2) site, where O most likely represents a conserved aspartate and a solvent molecule. The same structure was found for Co(II)-substituted A. aeolicus LpxC, although in this case it is possible that the coordination sphere may expand to include a fifth low-Z ligand. EXAFS data were also measured for the Escherichia coli LpxC enzyme. When a single Co(II) is substituted for Zn(II) in the active site of E. coli LpxC, EXAFS data show the same ligand environment as is found for the P. aeruginosa and A. aeolicus enzymes. However, the EXAFS data for E. coli LpxC with two zinc ions bound per protein, with the second Zn(II) acting as an inhibitory metal, demonstrates that the inhibitory metal is bound to at least two high-Z (sulfur, presumably thiolate, or chlorine) ligands. Results of the outer-shell scattering analysis, combined with previous studies of the LpxC enzyme, indicate a novel zinc binding motif not found in any previously studied zinc metalloproteins.     

Interactions of insulin-mimetic zinc(II) complexes with cell constituents: glutathione and ATP

Ternary complex formation of some potent insulin-mimetic zinc(II) complexes of bidentate ligands: maltol and 3-hydroxy-1,2-dimethyl-pyridinone with (O,O), 2-picolinic acid and 6-methylpicolinic acid with (N,O) and the tridentate 2,6-dipicolinic acid with (O,N,O) coordination modes was studied in aqueous solutions by pH-potentiometry and spectroscopic (UV, CD, ESI-MS) methods in the presence of critical cell constituents such as l-glutathione reduced (GSH) and adenosine 5′-triphosphate (ATP). Results showed that formation of the ternary complexes was hindered in the case of 2,6-dipicolinic acid, especially with ATP, while it was favoured with the bidentate ligands in the physiological pH range. Driving force of the formation of mixed-ligand species was found to be a more enhanced coordination of GSH and ATP as second ligands in the ternary complexes than in their binary ones due to steric and electrostatic reasons. The mitochondrial dehydrogenase activity of the zinc(II) complexes, as an indirect indicator for the glucose intake, was measured on Mono Mac and 3T3-L1 adipocyte cell lines. The activity of the complexes up to ∼10-100 μM concentration was in the range of the effect of 0.75-1.5 μM insulin, while at higher concentration it was broken down due to the sensitivity of the cells to toxicity of the complexes.     

Cobalt(II) and zinc(II) binding to a ferredoxin maquette

We have examined the Co(II) and Zn(II) affinity of the prototype ferredoxin maquette ligand, NH(2)-KLCEGG.CIACGAC.GGW-CONH2 (IAA), which was originally designed to bind a [4Fe-4S] cluster. UV-Vis spectroscopy demonstrates tight 1:1 complex formation between Co(II) and IAA. The intensity of the S-->Co(II) charge transfer bands at 304 and 340 nm and the ligand field bands between 630 and 728 nm indicate Co(II) coordination by the four cysteine thiolates of IAA in a pseudo-tetrahedral geometry. A dissociation constant value of 5.3 microM was determined for the Co(II)-IAA complex at pH 6.5. Zn(II) readily displaces Co(II) from IAA as evinced by loss of the Co(II) spectral features. The dissociation constant for Zn(II), 20 pM at pH 6.5, was determined be competition experiments with Co(II)-IAA. These results demonstrate that the ferredoxin maquette ligand is an excellent ligand for Zn(II).     

Dinuclear zinc(II) complex with novel tripodal polyamine ligand: synthesis, structure and kinetic study of carboxy ester hydrolysis

An imidazole-containing tripodal polyamine ligand N(1)-(2-aminoethyl)-N(1)-(2-imidazol-1-ylethyl)-ethane-1,2-diamine (L) was prepared and its dinuclear zinc(II) complex [Zn(L)(H(2)O)](2)(ClO(4))(4).4H(2)O (1) was obtained and examined as a catalyst for the hydrolysis of 4-nitrophenyl acetate (NA). X-ray crystal structure analysis of the complex revealed that the complex features a dinuclear cation unit with a Zn...Zn distance of 8.34A and both Zn(II) centers adopt distorted trigonal-bipyramid geometry. The solution complexation investigation performed at 25 degrees C by means of potentiometric titration revealed that the mononuclear species [ZnL](2+) is predominating in the pH rage of 7.0-9.7 in the solution and the pK(a1) for the Zn-bound water is 8.50+/-0.01. Complex 1 promoted hydrolysis of NA showed a second-order rate constant of 0.046+/-0.004 M(-1)s(-1) at pH 9.0 in 10% (v/v) CH(3)CN aqueous solution at 25 degrees C. The pH-rate profile for the second-order rate constant of NA hydrolysis with complex 1 gave a sigmoidal curve. And the results show that in the hydrolysis process the two Zn(II) centers of the dinuclear deprotonated species do not cooperate with each other and the Zn-bound hydroxide servers as reactive nucleophile toward the ester.     

The Pharmacology of the Insulinomimetic Effect of Zinc Complexes

In developing new insulinomimetic zinc(II) complexes with different coordination structures and with a blood glucose-lowering effect to treat type 2 diabetic animals, we found a potent bis(maltolato)zinc(ll) complex, Zn(mal)₂. Using the complex as the leading compound, we examined the in vitro and in vivo structure-activity relationships of Zn(mal)₂ and its related complexes in respect to the inhibition of free fatty acids (FFA) release and the enhancement of glucose uptake in isolated rat adipocytes treated with epinephrine (adrenaline), and hypoglycemic activity. Among the compounds tested, a new Zn(II) complex with allixin that was isolated from garlic, bis(allixinato)Zn(II), Zn(alx)₂, was found to exhibit the highest insulin-mimetic and hypoglycemic activities in type 2 KK-A^y diabetic mice. On the basis of the results, Zn(alx)₂, complex was proposed to be a potent candidate for the treatment of type 2 diabetes.     

Zinc(II) complexes with potent cyclin-dependent kinase inhibitors derived from 6-benzylaminopurine: synthesis, characterization, X-ray structures and biological activity

The synthesis, characterization and biological activity of the first zinc(II) complexes with potent inhibitors of cyclin-dependent kinases (CDKs) derived from 6-benzylaminopurine are described. Based on the results following from elemental analyses, infrared, NMR and ES+MS (electrospray mass spectra in the positive ion mode) spectroscopies, conductivity data, thermal analysis and X-ray structures, the tetrahedral Zn(II) complexes of the compositions [Zn(Olo)Cl(2)](n) (1), [Zn(iprOlo)Cl(2)](n) (2), [Zn(BohH(+))Cl(3)] x H(2)O (3) and [Zn(iprOloH(+))Cl(3)] x H(2)O (4) have been prepared, where Olo=2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine (Olomoucine), iprOlo=2-(2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (i-propyl-Olomoucine), Boh=2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine (Bohemine). The 1D-polymeric chain structure for [Zn(Olo)Cl(2)](n) (1) as well as the monomeric one for [Zn(BohH(+))Cl(3)] x H(2)O (3) and [Zn(iprOloH(+))Cl(3)] x H(2)O (4) have been revealed unambiguously by single crystal X-ray analyses. The 1D-polymeric chain of 1 consists of Zn(Olo)Cl(2) monomeric units in which the Zn(II) ion is coordinated by two chlorine atoms and one oxygen atom of the 2-hydroxyethylamino group of Olomoucine. The next monomeric unit is bonded to Zn(II) through the N7 atom of a purine ring. Thus, each of Zn(II) ions is tetrahedrally coordinated and a ZnCl(2)NO chromophore occurs in the complex 1. The complexes 3 and 4 are mononuclear species with a distorted tetrahedral arrangement of donor atoms around the Zn(II) ion with a ZnCl(3)N chromophore. The corresponding CDK inhibitor, i.e., both Boh and iprOlo, is coordinated to Zn(II) via the N7 atom of the purine ring in 3 and 4. The cytotoxicity of the zinc(II) complexes against human melanoma, sarcoma, leukaemia and carcinoma cell lines has been determined as well as the inhibition of the CDK2/cyclin E kinase. A relationship between the structure and biological activity of the complexes is also discussed.     

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.     

Synthesis and crystal structures of five-coordinated β-pyrrole tetra(phenyl/cyano) substituted zinc(II)-tetraphenylporphyrins

Crystal structures of a series of 2,3,5,10,12,13,15,20-octaphenylporphinato zinc(II) complexes with varying axial ligands have been examined to elucidate the role of fifth ligand on the stereochemistry of the porphyrin macrocycle. The nonplanarity of the macrocycle varies in the order, ZnOPP < ZnOPP(pyridine) < ZnOPP(H₂O). The electron deficient porphyrin complex of five-coordinated Zn(II), ZnTPP(CN)₄(CH₃OH) showed enhanced nonplanarity of the macrocycle and it is less than that of ZnOPP(H₂O)·TCE complex. Normal coordinate structure decomposition analysis of the out-of-plane displacement of the porphyrin ring in these structures revealed negligible wave distortion in planar four-coordinated ZnOPP and saddle, ruffled and domed distortions in other five-coordinated Zn(II)-porphyrins. The pronounced distortion of the macrocyclic ring in these structures is possibly due to the axial ligand, solvate and/or intermolecular interactions compared to steric crowding of the peripheral substituents.     

The Analysis of Cu(II)/Zn(II) Cyclopeptide System as Potential Cu,ZnSOD Mimic Center

In this paper are presented the features of copper (II) and zinc (II) heteronuclear complexes of the cyclic peptide—c(HKHGPG)₂. The coordination properties of ligand were studied by potentiometric, UV–Vis and CD spectroscopic methods. These experiments were carried out in aqueous solutions at 298 K depending on pH. It turned out that in a physiological pH dominates Cu(II)/Zn(II) complex ([CuZnL]⁴⁺) which could mimic the active center of superoxide dismutase (Cu,ZnSOD). In next step we performed in vitro research on Cu,ZnSOD activity for [CuZnL]⁴⁺ complex existing in 7.4 pH by the method of reduction of nitroblue tetrazolium (NBT). Also mono- and di-nuclear copper (II) complexes of this ligand were examined. The ability of inhibition free radical reaction were compared for all complexes. The results of these studies show that Cu(II) mono-, di-nuclear and Cu(II)/Zn(II) complexes becoming to new promising synthetic superoxide dismutase mimetics, and should be considered for further biological assays.     

Stabilization of the non-canonical adenine-adeninium base pair by N(7) coordination of Zn(II)

A new zinc (II) compound with 9-ethyladenine (9-EtA) of formula [Zn(9-EtA-N7)Cl(3)](9-EtAH) has been synthesized and characterized by X-ray diffraction. Its X-structure consists of an Zn(II) anionic complex and 9-ethyladeninium as counteranion. The Zn(II) complex shows a distorted tetrahedral geometry in which three Cl and an 9-EtA coordinates through N(7) position are the ligands. An indirect chelation via intramolecular H-bond between N(6)H and an Cl ligand is present in the complex. The network of [Zn(9-EtA-N7)Cl(3)](9-EtAH) shows interesting features. Thus, self-association of coordinated adenine-adeninium takes place by H-bonding of N(6)-H...N(1) and N(6)-H...N(7), leading to a polymeric ribbon-like 1D supramolecular arrangement. Ab initio calculations have been applied in order to study the stability of the adenine-adeninium interaction due to the coordination of the Zn(II) to the N(7) position and to compare experimental and theoretical structural data.     

Synthesis, crystal structures, and anti-convulsant activities of ternary [Zn(II)(3,5-diisopropylsalicylate)(2)], [Zn(II)(salicylate)(2)] and [Zn(II)(aspirinate)(2)] complexes

Following observations that bis(3,5-diisopropylsalicylato)diaquazinc(II), [Zn(II)(3,5-DIPS)(2)(H(2)O)(2)], had anti-convulsant activity, bis(acetylsalicylate)diaquazinc(II), [Zn(II)(aspirinate)(2)(H(2)O)(2)], and the Zn(II) ternary 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (neocuproine, NC) or dimethyl sulfoxide (DMSO) complexes of Zn(II)3,5-diisopropylsalicylate, salicylate, and acetylsalicylate were synthesized and spectroscopically characterized. Anti-convulsant and Rotorod toxicity activities of these complexes were determined to examine their anti-convulsant and undesirable central nervous stimulant or depressant activities of these Zn(II) non-steroidal anti-inflammatory agent complexes. Bis(3,5-diisopropylsalicylato)-1,10-phenanthorlinezinc(II), [Zn(II)(3,5-DIPS)(2)(phen)], (1) has one bidentate phen ligand and two mono-deprotonated 3,5-DIPS ligands. One of the carboxylates bonds in an asymmetric chelating mode. The Zn(II) atom exhibits a distorted bicapped rectangular pyramidal environment N(2)O(2)OO (4+1+1 *). In the neocuproine complex, bis(3,5-diisopropylsalicylato)-2,9-dimethyl-1,10-phenanthorlinezinc(II), [Zn(II)(3,5-DIPS)(2)(NC)] (2), the Zn(II) atom has a much more distorted bicapped rectangular pyramidal environment, N(2)O(2)O(2) (4+2 *), compared to 1. The two carboxylate ligands exhibit the same asymmetric coordinating mode with longer metalloelement-oxygen bond distances compared to 1. The space group of [Zn(II)(aspirinate)(2)(H(2)O)(2)] (3), which has been reported as Cc is corrected to C2/c. The zinc atom exhibits a (4+2 *) bicapped square pyramidal environment. While the two ternary phenanthroline-containing complexes, 1 and 2, evidenced weak protection against maximal electroshock (MES)- and subcutaneous Metrazol (scMET) induced seizures, [Zn(II)(3,5-DIPS)(2)(DMSO)(2)], [Zn(II)(aspirinate)(2)(H(2)O)(2)], and bis(salicylato)-1,10-phenanthorlinezinc(II), [Zn(II)(salicylate)(2)(phen)], were found to be particularly useful in protecting against MES and scMET seizures and [Zn(II)(aspirinate)(2)(H(2)O)(2)] and [Zn(II)(salicylate)(2)(phen)] were found to have activity in protecting against Psychomotor seizures, without causing Rotorod toxicity. Activities of these and other Zn(II) complexes of non-steroidal anti-inflammatory agents are consistent with the well-known anti-inflammatory responses of Zn(II)-dependent enzymes. There was also some evidence of Rotorod toxicity consistent with a mechanism of action involving sedative-hypnotic activity of recognized anti-epilepticdrugs.