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.     

Crystal structures, spectral and magnetic properties of cobalt(II) pyridinecarboxylates: A novel polymeric chain in {[{2,6-(MeO)2nic}2(H2O)2Co(μ-H2O)Co(H2O)4(μ-H2O)]{2,6-(MeO)2nic}2 · 6H2O}n

Synthesis and characterization of two new cobalt(II) complexes, namely monomeric [Co(2-MeSnic)₂(H₂O)₄] · 4H₂O (2-MeSnic is 2-methylthionicotinate) and polymeric {[{2,6-(MeO)₂nic}₂(H₂O)₂Co(μ-H₂O)Co(H₂O)₄(μ-H₂O)]{2,6-(MeO)₂nic}₂ · 6H₂O}_n (2,6-(MeO)₂nic is 2,6-dimethoxynicotinate), are reported. The characterizations were based on elemental analysis, infrared and electronic spectra as well as magnetic measurements. Crystal structures of both complexes have been determined. In both of them - ([Co(2-MeSnic)₂(H₂O)₄] · 4H₂O and {[{2,6-(MeO)₂nic}₂(H₂O)₂Co(μ-H₂O)Co(H₂O)₄(μ-H₂O)]{2,6-(MeO)₂nic}₂ · 6H₂O}_n) - the Co^II atom is six-coordinated. In the 2nd complex, there are two nonequivalent Co^II central atoms, involved in forming a linear polymeric chain with alternating cationic and neutral part. One of them is octahedrally coordinated by a carboxyl oxygen atom of 2,6-(MeO)₂nic, two water molecules and the corresponding centrosymmetrically located atoms. The second Co^II atom is also octahedrally coordinated by six water molecules. Both coordination polyhedra are bridged by a water molecule. The charge of the cationic part is compensated for by two independent anionic 2,6-(MeO)₂nic units. The structure is held together by a complicated system of hydrogen bonds.     

Physiological levels of glutathione enhance Zn(II) binding by a Cys4 zinc finger

Using fluorescence and UV-vis spectroscopies and mass spectrometry, we demonstrated that the presence of physiological levels of reduced glutathione enhances the binding of Zn(II) to XPAzf, a Cys4 zinc finger peptide derived from the XPA protein, by means of formation of a ternary complex of a general formula ZnXPAzf[GSH]. Similar complexes were also indicated by ESI-MS for isostructural Co(II)- and Cd(II)-substituted XPAzf. The observed enhancement of the Zn(II) binding to XPAzf by a factor of 50 over the physiological range of GSH concentrations of 1-20 mM corresponds to a dissociation constant of GSH from the ZnXPAzf[GSH] complex of 0.05 μM. This effect may account for an apparent discrepancy between relatively low Zn(II) binding constants measured in vitro for many zinc fingers, and the requirement of tight Zn(II) binding enforced by intracellular zinc buffering by the thionein/metallothionein couple.     

A comparison of the gas, solution, and solid state coordination environments for the Cu(II) complexes of a series of linear aminopyridine ligands with varying ratios of 5- and 6-membered chelate rings

The synthesis and characterization of the copper(II) complexes of a series of tetradentate, pentadentate and hexadentate aminopyridine ligands that contain ethylenediamine and/or propylenediamine groups are described. The ligands include: 1,12-bis(2-pyridyl)-2,5,8,11-tetraazadodecane, TRIEN-pyr; 1,13-bis(2-pyridyl)-2,5,9,12-tetraazatridecane, DIEN-PN-pyr; 1,14-bis(2-pyridyl)-2,6,9,13-tetraazatetradecane, DIPN-EN-pyr; 1,15-bis(2-pyridyl)-2,6,l0,14-tetraazapentadecane, TRIPN-pyr; 1,9-bis(2-pyridyl)-2,5,8-triazanonane, DIEN-pyr; 1,11-bis(2-pyridyl)-2,6,10-triazaundecanenane, DIPN-pyr; 1,6-bis(2-pyridyl)-2,5-diazahexane, EN-pyr; and 1,7-bis(2-pyridyl)-2,6-diazaheptane, PN-pyr. The following methods were used to determine the binding geometries of the copper(II) complexes in the solid, solution, and gas phases: magnetic susceptibility measurements, absorption spectroscopy, EPR spectroscopy, electrochemistry, and electrospray ionization mass spectrometry. An X-ray structure was determined for the DIPN-pyr complex. The solid state structures were all found to be monomeric Cu(II) complexes with the coordination number set by the denticity of the ligand while the solution structures of all of the complexes except those with TRIPN-pyr and DIPN-pyr were found to be square pyramidal or elongated octahedral. The TRIPN-pyr and DIPN-pyr complexes showed considerable trigonal bipyramidal distortions. The gas phase data showed that the substitution of 6-membered for 5-membered chelate rings helped the ligand span more coordination sites. The TRIEN-pyr complex was 4- or 5-coordinate compared to the 5- or 6-coordination seen with the other three hexadentate ligands, and the DIPN-pyr complex was weakly 5-coordinate as compared to the 4-coordinate DIEN-pyr complex. The preferred structures of the ligands were consistent with their electrochemical behavior which showed the stability of the Cu(II) complex decreased in the order: DIPN-EN-pyr, TRIEN-pyr, DIEN-PN-pyr > DIEN-pyr > DIPN-pyr > TRIPN-pyr >  PN-pyr > EN-pyr.     

Coordination behavior of three geometric isomers of indole-based S-benzyldithiocarbazone ligands towards nickel, zinc and cadmium divalent ions

Three indolyl-imine ligands have been synthesized through the condensation of S-benzyldithiocarbazate with indole-2-carbaldehyde, indole-3-carbaldehyde and indole-7-carbaldehyde. Treatment of these Schiff bases with acetate salts of Ni(II), Zn(II) and Cd(II) in ethanol yielded a series of complexes of 2:1 type (ligand/metal ratio) in which the ligands coordinated to the metal ions as monoanionic NS bidentate chelates. While the 2-imineindole and 3-imineindole formed the expected five-membered chelate rings, the X-ray crystal structure of [Cd(HL³)(py)₂], (HL³ = the mono-deprotonated 7-imineindole), revealed an unusual mode of coordination, namely formation of four-membered rings with the metal atom. Reaction of the 7-imineindole with the metal ions in the presence of potassium hydroxide produced complexes of the type [M(L³)(H₂O)] in which the Schiff base acts as a dianionic NNS tridentate ligand.     

Synthesis and structural characterization of five-, six-, and seven-coordinate mononuclear manganese(II) complexes with N-tridentate ligands

A series of four mononuclear manganese (II) complexes with the N-tridentate neutral ligands 2,2^′:6,2^′′-terpyridine (terpy) and N,N-bis(2-pyridylmethyl)ethylamine (bpea) have been synthesized and crystallographically characterized. The complexes have five- to seven-coordinate manganese(II) ions depending on the additional ligands used. The [Mn(bpea)(Br)₂] complex (1) has a five-coordinated manganese atom with a bipyramidal trigonal geometry, while [Mn(terpy)₂](I)₂ (2) is hexa-coordinated with a distorted octahedral geometry. Otherwise, the reactions of Mn(NO₃)₂ · 4H₂O with terpy or bpea afforded novel seven-coordinate complexes [Mn(terpy)(NO₃)₂(H₂O)] (3) and [Mn(bpea)(NO₃)₂] (4), respectively. 3 has a coordination polyhedron best described as a distorted pentagonal bipyramid geometry with one nitrate acting as a bidentate chelating ligand and the other nitrate as a monodentate one. 4 possesses a highly distorted polyhedron geometry with two bidentate chelating nitrate ligands. These complexes represent unusual examples of structurally characterized complexes with a coordination number seven for the Mn(II) ion and join a small family of nitrate complexes.     

Synthesis and characterization of a series of diphenyldipyrazolylmethane complexes with zinc(II)

The zinc(II) coordination chemistry of a series of diphenyldipyrazolylmethane ligands was explored using ¹H NMR and single crystal X-ray diffraction. Unsubstituted diphenyldipyrazolylmethane (dpdpm), diphenylbis(3-methylpyrazolyl)methane (dpdp′m), and diphenylbis(3,5-dimethylpyrazolyl)methane (dpdp″m) were reacted with Zn(NO₃)₂ to afford Zn(dpdpm)(NO₃)₂, Zn(dpdp′m)(NO₃)₂ and Zn(Pz″)₂(NO₃)₂ where Pz″ = 3,5-dimethylpyrazole, respectively. All attempts to isolate Zn(dpdp″m)(NO₃)₂ with the intact dpdp″m ligand were unsuccessful due to decomposition of the ligand. These bidentate ligands support the formation of 1:1 ligand to metal complexes and structurally model the two histidine coordination mode common in zinc proteins.     

Preparation and crystal structure of two novel cadmium (II)-trimesates, Cd(HTMA)(NC5H5)2 · 0.5CH3OH · 0.5DMF and Cd(HTMA) · 2H2O

Two novel complexes, Cd(HTMA)(NC₅H₅)₂ · 0.5CH₃OH · 0.5DMF (1) and Cd(HTMA) · 2H₂O (2), of cadmium (II)-trimesates are obtained from slow vapor diffusion and urea hydrolysis, respectively. The Cd(II) centers in the two complexes are bridged by three separate HTMA³⁻ ligands using a same coordination fashion, which contains one monodentate and two chelating bidentate carboxyl groups to form the herringbone-like motif. The herringbone-like motif is further interlinked to construct the two-dimensional Cd(II)-HTMA layer, which is stacked by mutual π-stacking of pyridines for 1 and by hydrogen bond of waters for 2. Thermal stabilities of the two complexes were investigated and the results indicated that Cd(II)-TMA layers in the two complexes are stable still upon 190 °C.     

Complexation thermodynamics and the structure of the binary and the ternary complexes of Am, Cm and Eu with CDTA and CDTA + IDA

The stability constants and the thermodynamic parameters of the formation of the binary complexes of trivalent Am³⁺, Cm³⁺ and Eu³⁺ with CDTA and of their ternary complexes with CDTA + IDA were determined by solvent extraction measurements in aqueous solutions of I = 6.60 m (NaClO₄) at temperatures of 0-60 °C. The endothermic enthalpy and the positive entropy values reflect the significant effects of cation dehydration and of the rigidity of the ligand structure in the formation of these complexes. TRLFS and NMR (¹H and ¹³C) data provided information on the structure of the ternary complexes in solution. The size and rigidity of CDTA affect the binding mode of IDA in the complexation of M(CDTA)(IDA)(H₂O)³⁻ and M(CDTA)(IDA)³⁻ in which IDA has a bidentate coordination mode in the former and a tridentate coordination mode in the latter.     

Ternary uranyl hydroxo acetate complexes: A computational study of structure, energetics, and stability constants

We studied computationally uranyl monohydroxo monoacetate complexes in aqueous solution using a scalar relativistic all-electron density functional method. Such ternary uranyl complexes may serve as models of ternary uranyl humate complexes which are important for the speciation of uranyl in the environment. As for simple uranyl monocarboxylate complexes, we calculated bidentate coordination to be slightly preferred due to entropy and solvation effects. Compared to uranyl acetate, uranyl hydroxo acetate exhibits an elongated uranyl bond and a short U-OH bond of ∼214 pm. The latter may provide a signature for direct identification of such ternary complexes by EXAFS. As expected from the lower charge of uranyl monohydroxide, complexation by acetate is less exoenergetic than acetate complexation of uranyl. In contrast, experimental complexation constants of uranyl humate and uranyl hydroxo humate are quite similar. Thus, one may question the interpretation of experimental results that assign simple ternary complexes as result of uranyl humate complexation at neutral pH.     

Interaction of folic acid and some matrix metalloproteinase (MMP) inhibitor folate-γ-hydroxamate derivatives with Zn(II) and human serum albumin

Human serum albumin binding of folic acid and its γ-hydroxamate/carboxylate derivatives was studied by ultrafiltration and spectrofluorimetry, and it was found that the ligands exhibit a moderate binding (K_D ~ 2-50 μM), and the folate-γ-phenylalanine represents the highest conditional binding constant towards albumin. This feature may have importance in the serum transport processes of these ligands. Interaction of folic acid and its derivatives with Zn(II) was investigated in aqueous solution to obtain the composition and stabilities of the complexes by the means of pH-potentiometry, ¹H NMR and electrospray ionization mass spectrometry, together with the characterization of the proton dissociation processes and the hydro-lipophilic properties of the ligands. The formation of mono-ligand complexes was demonstrated in all cases and the contribution of the glutamyl carboxylates to the coordination was excluded. Binding of folic acid and its γ-carboxylate derivatives to Zn(II) via the pteridine moiety is suggested, while the (O,O) coordination fashion of the folate-γ-hydroxamate ligands has importance in their inhibitory activity against Zn(II)-containing matrix metalloproteinases. It was found that the enzyme inhibition of these folate-γ-hydroxamate ligands is mainly tuned by other features, such as the lipophilic character rather than the Zn(II)-chelate stability.     

Nano-sized titanium(IV) ternary and quaternary complexes with electron-rich oxygen-based bidentate ligands

Some novel ternary and quaternary complexes of titanium(IV) of general formula [Ti(acac)Cl_3−n(OOCR)_n] (R = C₁₅H₃₁ or C₁₇H₃₅ and n = 1-3) have been synthesized by stepwise substitution of chloride ions of [Ti(acac)Cl₃] by straight chain carboxylic acid anions. The complexes are characterized by their elemental analyses, spectral (infrared, FAB mass, ¹H NMR and powder XRD) studies, molecular weight determination and molar conductance measurements. Infrared spectra suggested bidentate chelating nature of both acetylacetonate and carboxylate anions in the complexes. Monomeric nature of the complexes was confirmed by their molecular weight determination and FAB mass spectra. Molar conductance values indicated the complexes to be non-electrolytes in DMF. The complexes exhibited high resistance to hydrolysis. Their powder XRD data indicated the nano-size for the complexes. The coordination number of titanium(IV) in these complexes were found to be six, seven and eight which has been discussed in detail.     

Nickel(II) and zinc(II) dimonensinates: Single crystal X-ray structure, spectral properties and bactericidal activity

Mononuclear transition metal complexes of the polyether ionophorous antibiotic monensin (monensic acid, MonH) with nickel(II) and zinc(II) were prepared and characterized using single crystal X-ray diffraction and spectral methods. Monensin complexes crystallize as [Ni(Mon)₂(H₂O)₂]·H₂O·5MeCN (1) and [Zn(Mon)₂(H₂O)₂]·H₂O·4.5MeCN (2), respectively, in the monoclinic space group P2₁. Compounds 1 and 2 consist of two monoanionic monensic acid ligands (monensinates) bound in a bidentate coordination mode to the transition metal ion. The metal center is placed in an octahedral environment with monensin anions occupying the equatorial plane of complexes via oxygens of carboxylate and hydroxyl groups located at the both ends of ionophore molecule. The strongly folded antibiotic anions are supported by intramolecular H-bonds, most of them originating from the two aqua ligands attached to the metal(II) ions in axial positions and completing their 6-fold coordination. The bioactivity assay reveals that the presence of divalent metal ion in the monensin complexes influences the biological properties of the ligand and should be taken into account when discussing its mode of action.     

The synthesis, crystal and molecular structures of two saccharinate-metal complexes with dipyridylamine (dipyr) as a co-ligand

The complexes [Cd(dipyr)₂(sac)(H₂O)] sac·H₂O 1 and [Hg(dipyr)(sac)₂] 2, where dipyr = dipyridylamine and sac = saccharinate, have been synthesised, and fully characterised by single-crystal X-ray diffraction at 120 K. The geometry around Cd in 1 is approximately octahedral, with the metal coordinated by two bidentate dipyr ligands, one N-bonded sac and one H₂O molecule; the second sac forms the counter-ion, and there is also a water of crystallisation. An extensive H-bonded network is formed. In the anhydrous Hg complex 2, the metal has approximately tetrahedral geometry, with coordination from a bidentate dipyr ligand and two N-bonded sac groups. H-bonding interactions are again extensive, even without the presence of H₂O molecules in the structure, leading to chains along the a-axis.     

Robust building blocks for inorganic crystal engineering

We have prepared two ligands, 4- and 5-carboxylic acid pyrimidine, and synthesized and crystallographically characterized seven coordination complexes thereof. The need for potentially structurally disruptive counterions is eliminated by deprotonation of the carboxylic acid moieties; the carboxylates present in each structure act as counterions and balance the charge on the divalent metal ions leading to charge-neutral complex ions. The four new M(II)-complexes with 4-carboxylic acid pyrimidine (M = Ni, Cu, Zn, and Co) are isostructural as are the three M(II) complexes with 3-carboxylic acid pyrimidine (M = Ni, Cu, and Zn), indicating robust and reliable coordination modes for both ligands.     

Coordination chemical studies on metalloenzymes. IX. Properties of the ternary complex between cobalt(II)-bovine carbonic anhydrase and bidentate ligands

The spectrum, thermodynamic parameters, and proton longitudinal relaxation time of the ternary complex between various bidentate ligands (2-pyridinecarboxylate, 2-quinolincarboxylate, 8-quinolinecarboxylate, and 2-pyridylacetate) and cobalt(II)-bovine carbonic anhydrase were measured to clarify the nature of the ternary complex. The formation constants of the ternary complexes of bidentate ligands are in the order of (2-pyridinecarboxylate ? 8-quinolinecarboxylate ? 2-quinolinecarboxylate ≈2-pyridylacetate). The degree of the shift of the band characteristic of five-coordinate species at 13-15 kcm^-1 (cm^-1 × 10^-3) and that of the higher energy band at 21–22 kcm^-1 decrease almost in the same order. These results are explained on the basis of the contribution of the bond formation between the nitrogen atom of the heterocyclic ring of ligands and cobalt ion. The formation constants of the ternary complex of bidentate ligands were compared to the stability constants of various ligands with a cobalt ion but there is no correlation in these values. The rate constant of break-up of the ternary complex was discussed on the coordination geometry of the ternary complex on the basis of the degree of the distortion.     

Nickel and palladium complexes bearing ortho-phenoxy modified anilido-imine ligands: Drastic steric effect on coordinated geometry, and catalytic property toward olefin polymerization

A series of new nickel complexes and palladium complexes bearing ortho-phenoxy modified anilido-imine ligands have been synthesized and characterized. X-ray diffraction analyses of the single crystal structures reveal that there are no direct metal-O interactions in all of the complexes. The steric hindrance of complexes has an importance influence on their coordinated geometries. The bulky complexes with 2,6-diisopropylphenyl substituent exist as a dimers with bromine-bridged structure while those with 2,6-dimethylphenyl or phenyl substituents adopt a distorted tetrahedral geometry with four nitrogen atoms of two anilido-imine ligands. The nickel complexes exhibited high activity up to 7.33 × 10⁶ g/(mol of Ni · h) and palladium complexes showed very high activity up to 2.63 × 10⁸ g/(mol of Pd · h) for norbornene polymerization with methylaluminoxane as cocatalyst. The nickel catalysts were attempted to polymerize ethylene at atmosphere pressure, however, only oligomers were produced.     

Coordination abilities of substituted β-aminophosphonates towards Cu and Zn ions

The formation constants of equimolar and bis-chelate copper(II) and zinc(II) complexes with three aliphatic and four aromatic-substituted β-aminophosphonates have been determined in water solution by potentiometric studies. Spectroscopic parameters clearly indicate involvement of {NH₃, PO₃ ²⁻} in both metal ions coordination. The comparison of the stability constants reveals slightly higher coordination power of the aliphatic-substituted β-aminophosphonic acids, which may be due to the higher basicity of their amino groups. All studied ligands are more effective in Cu²⁺ and Zn²⁺ coordination than phosphonic analogue of simple β-amino acid.     

Formation of coordination polymer and molecular complex of 4,4′-bipyridyl-N,N′-dioxide of manganese and zinc

A 1D-coordination polymer [{Mn₃(C₆H₅COO)₆(BPNO)₂(MeOH)₂}(MeOH)₂]_n (1) having benzoate as the anionic ligand and 4,4′-bipyridyl-N,N′-dioxide (BPNO) as bridging ligand is synthesized by reacting benzoic acid with manganese(II) acetate tetrahydrate followed by reaction with 4,4′-bipyridyl-N N′-dioxide. The bridging bidentate BPNO ligands in this coordination polymer along with the benzoate bridges hold the repeated units. The chain like structure in one dimension by benzoate bridges are connected to each other through the μ³-η²:η¹ bridges of BPNO ligands. This coordination polymer can be transformed to a molecular complex [Mn(H₂O)₆](C₆H₅COO)_2.4BPNO (2). In this complex the BPNO remains outside the coordination sphere but they are hydrogen bonded to water molecules to form self assembled structure. The reaction of 3,5-pyrazoledicarboxylic acid (L₁H2) and BPNO with manganese(II) acetate or zinc(II) acetate led to molecular complexes with composition [M₂(L₁)₂(H₂O)₆].BPNO·xH₂O {where M = Mn(II) (3), Zn(II)(4)}. These molecular complexes of BPNO are characterised by X-ray crystallography. The complexes 3-4 are binuclear carboxylate complexes having M₂O₂ core formed from carboxylate ligands with two metal ions.     

Self-assembled synthesis, characterization and antimicrobial activity of zinc(II) salicylaldimine complexes

One-pot metal promoted reactions between salicylaldehyde and 4-methyl-1,3-phenylenediamine in the presence of metal salts acting as template agents yield zinc(II) salicylaldimine complexes containing N,N′-bis(salicylidene)-4-methyl-1,3-phenylenediamine (H₂L) as a result of the [2 + 1] Schiff base condensation. The complexes of formula [Zn(HL)Cl(H₂O)₂] · C₂H₅OH and [Zn(H₂L)₂Cl(NO₃)(H₂O)] · CH₃OH were characterized as powder solids and in solution by spectroscopic methods (IR, ¹H and ¹³C NMR, FAB-MS, ESI-MS, UV-Vis), thermogravimetric and elemental analysis, potentiometry, and tested for antimicrobial activity against Staphylococcusaureus in a minimum inhibitory concentration (MIC) experiment. In these two powder solid species, the salicylaldimine, formed in a self-assembly process, acts in two different coordination modes: as monodeprotonated bidentate chelator with an N,O donor set or as a neutral monodentate using exclusively oxygen as the donor atom without involving the nitrogen atoms in the coordination. However, crystals of these two complexes are isomorphous, with 1:2 metal:ligand stoichiometry, and display the latter, relatively rare coordination pattern. In solution, the presence of a 1:1 complex of monodeprotonated state is only detected. The complexes exhibit antimicrobial activity against S.aureus.