Stabilization of the cobalt coordination site in transmetalation processes on dinuclear salen derivatives

Two dinuclear cobalt/copper compounds have been isolated from the reaction between N,N′-ethylenebis(salicylideniminato)cobalt(II), [Co(salen)], and copper(II) chloride in different conditions. The first one is a dinuclear cobalt(III)/copper(II) derivative, [Co(salen)Cl₂Cu(EtOH)₂Cl], 1, that have the cobalt atom six-coordinated to the four donor atoms of the salen ligand and to two chlorine atoms in a slightly distorted octahedral environment and the copper atom five-coordinated to the two bridging oxygen atoms of the salen ligand, two ethanol molecules and one extra chlorine atom. This compound is the only reported example of a cobalt/copper derivative with the cobalt maintaining the salen coordinative site, since the usual reaction takes place by a transmetalation process. This reaction is observed in the second derivative, [Cu(salen)CoCl₂], 2, where the copper atom displaces the cobalt from the salen cavity. The copper atom adopts a square-planar coordinative environment, while the cobalt is tetrahedrically coordinated to the two bridging oxygen and two chlorine atoms. Both compounds present several intermolecular contacts that increase the dimensionality in the crystal and some of which can transmit magnetic interactions. The magnetic properties confirm the structural picture, with isolated copper(II) centres in 1, where the cobalt(III) is in the low spin form, and with antiferromagnetically coupled S = ¹/₂ and S = ³/₂ centres in 2.     

Specificity of transport of bleomycin and cobalt-bleomycin in L5178Y cells

The mechanism of transport of [³H]peplomycin (PEP), a new member of bleomycin group antibiotics, was studied in cultured L5178Y mouse leukemic cells. Cobalt ions enhanced the uptake of PEP, but Cu, Zn, Fe(II) and Fe(III) had no effect. The initial rate of uptake of cobalt chelated PEP [PEP(Co)] was several times higher than that of free or Cu-chelated PEP and was temperature independent. A double reciprocal plot of the data demonstrated both saturable (K_m = 4.5 μM, V_max = 1.3 × 10^?18 mole/min/cell) and non-saturable components of the uptake of PEP(Co). The saturable component was inhibited specifically by cobalt chelated bleomycin analogs. PEP-chelates with metals other than cobalt, such as PEP(Cu) were metabolically unstable. These results suggest that bleomycin enters into cells as a metal chelate through a specific transport site.     

Synthesis,characterization and antitumor activity of some metal complexes of 3- and 5-substituted salicylaldehyde o-hydroxybenzoylhydrazones

Complexes of Mn(II), Fe(III), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Pt(II) with 3- and 5-substituted salicylaldehyde o-hydroxybenzoylhydrazones (XSBH, X = H, 3-NO₂, 3-CH₃O, 5-Cl, 5-Br, 5-CH₃ or 5-NO₂) have been prepared and characterized by elemental analysis, conductance measurements, magnetic susceptibilities (from room temperature down to liquid nitrogen temperature) and spectral studies. These studies indicate the following structures: monomeric, high-spin, distorted octahedral for Mn(XSBH)₂; monomeric, high-spin, five-coordinate for Fe(XSBH)SO₄·H₂O; dimeric, high-spin phenoxide bridged, five-coordinate for Fe(XSBH)Cl; dimeric, high-spin five-coordinate for Co(XSBH)Cl·2H₂O; dimeric low-spin, five-coordinate for Ni(XSBH)Cl·2H₂O; dimeric, four-coordinate for Zn(XSBH); and a square-planar structure for M(XSBH)Cl·H₂O (M = Cu(II) or Pt(II).Intermolecular antiferromagnetic exchange interactions are present in Fe(III) complexes, where the exchange parameter (J) is ca. −8.0 cm⁻¹ for these complexes. The Fe(III) complexes exhibit asymmetric quadrupole split doublets in their ⁵⁷Fe Mössbauer spectra. The asymmetry is found to be temperature dependent with relatively symmetrical doublets seen at low temperature. The polycrystalline ESR spectra of Cu(II) complexes are isotropic and indicate a d_x²−y² ground state in square-planar stereo-chemistry. All these metal complexes have been screened for their antitumor activity against the P 388 lymphocytic leukaemia test system in mice and enhanced antitumor activity relative to the free ligand was found but no significant activity at the dosages used.     

Isostructural M(RL)2(hfac)2 complexes with RL = 5-(4-[N-tert-butyl-N-aminoxyl]phenyl)pyrimidine

5-(4-(N-tert-Butyl-N-aminoxylphenyl))pyrimidine (RL, 4PPN) forms crystallographically isostructural and isomorphic pseudo-octahedral M(RL)₂(hfac)₂ complexes with M(hfac)₂, M = Zn, Cu, Ni, Co, and Mn. Multiple close contacts occur between sites of significant spin density of the organic radical units. Magnetic behavior of the Zn, Cu, Ni, Co complexes appears to involve multiple exchange pathways, with multiple close crystallographic contacts between sites that EPR (of 4PPN) indicates to have observable spin density. Powder EPR spectra at room temperature and low temperature are reported for each complex. Near room temperature, the magnetic moments of the complexes are roughly equal to those expected by a sum of non-interacting moments (two radicals plus ion). As temperature decreases, AFM exchange interactions become evident in all of the complexes. The closest fits to the magnetic data were found for a 1-D Heisenberg AFM chain model in the Zn(II) complex (J/k = (?)7 K), and for three-spin RL—M—RL exchange in the other complexes (J/k = (?)26 K, (?)3 K, (?)6 K, for Cu(II), Ni(II), and Co(II) complexes, respectively).     

Folding strategy to prepare Co(II)-substituted metallo-beta-lactamase L1

In an effort to overcome previous problems with the preparation of Co(II)-substituted metallo-β-lactamase L1, two strategies were undertaken. Attempts to prepare Co(II)-substituted L1 using biological incorporation resulted in an enzyme that contained only 1 Eq of cobalt and exhibited no catalytic activity. Co(II)-substituted L1 could be prepared by refolding metal-free L1 in the presence of Co(II), and the resulting enzyme contained 1.8 Eq of cobalt, yielded a UV-Vis spectrum consistent with 5-coordinate Co(II), and exhibited a k_cat of 63 s⁻¹ and K_m of 20 μM when using nitrocefin as the substrate. Pre-steady-state fluorescence and UV-Vis studies demonstrated that refolded, Co(II)-substituted L1 uses the same kinetic mechanism as Zn(II)-containing L1, in which a reaction intermediate is formed when using nitrocefin as substrate. The described refolding strategy can be used to prepare other Co(II)-substituted Zn(II)-metalloenzymes, particularly those that contain a solvent-exposable disulfide, which often causes oxidation of Co(II) to Co(III).     

Metal Complexes of 2,6-Diacetylpyridine Bis(thiosemicarbazone): their Preparation,Characterization and Antitumour Activity

Complexes of Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Pt(II) with 2.6-diacetylpyridine bis(thiosemicarbazone) (daptsc-H₂) have been isolated and characterized by elemental analysis, conductance measurements, magnetic susceptibilities (from room temperature to liquid nitrogen temperature), diffuse reflectance and infrared studies. On the basis of these studies a seven-coordinate structure for Zn(daptsc-H₂)(OAc)₂, a six-coordinate structure for M(daptsc-H₂)Cl₂ (MMn(II), Co(Il), Ni(II) or Cu(II)) and Fe(daptsc-H₂)SO₄, and a five-coordinate structure for Pt(daptsc) are suggested. ⁵⁷Fe Mössbauer spectra at 300 and 78 K also suggest a distorted octahedral structure with d_xy ground state for Fe(daptsc-H₂)SO₄ complex. All these metal(II) complexes have been screened for their antitumour activity in the P388 lymphocytic leukaemia test system in mice and showed enhanced antitumour activity relative to the free ligand.     

Co(II)-substituted Octopus vulgaris hemocyanin

Co(II)-substituted hemocyanin (Co(II)Hc) of the octopus, Octopus vulgaris, has been prepared by dialysis of apohemocyanin against Co(II·) ion and subsequent Chelex-treatment. The blue 50%-Co(II)Hc (half-apo Co(II)Hc), in which binuclear coppers are replaced in the hemocyanin by a single Co(II), exhibits two absorption maxima at 560 (?_Co=250) and 594 nm (?_Co=320 M^?1 cm^?1) and a shoulder near 610 nm, all of which are attributed to a dd transition of high spin Co(II) (S=3/2) with a tetrahedral geometry. The magnetic circular dichroism (MCD) spectrum in this region also suggests the existence of a tetrahedral Co(II) species in the protein. The visible absorption and MCD spectra of octopus 50%-Co(II)Hc are quite similar to those of squid 50%-Co(II)Hc described in the previous paper (S. Suzuki, J. Kino, M. Kimura, W. Mori and A. Nakahara, Inorg. Chim. Acta, 66, 41 (1982)). The formation of half-apo Co(II)Hc demonstrates that the binuclear copper sites in native octopus hemocyanin may differ from each other in coordination geometry, as in other molluscan hemocyanins, squid and snail hemocyanins. The coordination environment of the active-site Co(II) substituted for Cu in the octopus hemocyanin is the same as that of the corresponding active site of the squid hemocyanin.     

Thermodynamics of metal ion binding. 1. Metal ion binding by wild-type carbonic anhydrase

Understanding the energetic consequences of molecular structure in aqueous solution is a prerequisite to the rational design of synthetic motifs with predictable properties. Such properties include ligand binding and the collapse of polymer chains into discrete three-dimensional structures. Despite advances in macromolecular structure determination, correlations of structure with high-resolution thermodynamic data remain limited. Here we compare thermodynamic parameters for the binding of Zn(II), Cu(II), and Co(II) to human carbonic anhydrase II. These calorimetrically determined values are interpreted in terms of high-resolution X-ray crystallographic data. While both zinc and cobalt are bound with a 1:1 stoichiometry, CAII binds two copper ions. Considering only the high-affinity site, there is a diminution in the enthalpy of binding through the series Co(II) --> Zn(II) --> Cu(II) that mirrors the enthalpy of hydration; this observation reinforces the notion that the thermodynamics of solute association with water is at least as important as the thermodynamics of solute-solute interaction and that these effects must be considered when interpreting association in aqueous solution. Additionally, DeltaC(p) data suggest that zinc binding to CAII proceeds with a greater contribution from desolvation than does binding of either copper or cobalt, suggesting Nature optimizes binding by optimizing desolvation.     

Inductive influence of 4′-terpyridyl substituents on redox and spin state properties of iron(II) and cobalt(II) bis-terpyridyl complexes

A series of iron and cobalt bis-terpyridine (terpy) complexes were prepared with the general formula [M(R-terpy)₂](PF₆)₂, where M represents Co(II) and Fe(II), and R is the following terpyridine substituents in order of increasing electron-withdrawing behavior [(C₄H₈)N, (C₄H₉)NH, HO, CH₃O, CH₃-phenyl, H, Cl, CH₃SO, CH₃SO₂]. The complexes were prepared to investigate the extent of redox and spin state control that is attainable by simply varying the electron donating/withdrawing influence using a single substituent site on the terpyridine ligand. Cyclic voltammetry was used to assess the substituents influence on the M(III/II) redox couple. A plot of the M(III/II) redox potential (E_1/2) versus the electron donating/withdrawing nature of the substituents (Hammett constants), shows a strong linear trend for both metals; however, the substituents were observed to have a stronger influence on the Fe(III/II) couple. Solution magnetic susceptibility measurements at room temperature were carried out using standard NMR methodology (modified Evans method) where all of the Fe(II) complexes exhibited a diamagnetic, low spin (S = 0) behavior. In the cobalt series where R = H for [Co(R-terpy)₂]²⁺, the complex is known to be near the spin cross-over where the room temperature effective magnetic moment (μ_eff) in solution is ≈3.1 Bohr magnetons; however, in this study the μ_eff is observed to vary between 2.7 and 4.1 Bohr magnetons depending on the R-substituent.     

Magnetic properties of six-coordinated high-spin cobalt(II) complexes: Theoretical background and its application

In this contribution we study and analyse the influence of the different parameters involved in the magnetic susceptibility of six-coordinated high-spin Co(II) complexes. We propose an empirical expression to fit the magnetic susceptibility of polycrystalline samples of mononuclear Co(II) complexes with an axial distortion, the variable parameters being Δ (axial distortion), α (orbital reduction factor) and λ (spin–orbit coupling). This expression avoids solving the 12 × 12 matrix associated to the distortion of the ⁴T_1g term. In order to take into account the magnetic coupling (J) in the polynuclear Co(II) complexes, a perturbational approach is proposed to describe their magnetic susceptibility in the whole temperature range (2–300 K) as a function of J, Δ, α and λ. This approach is valid in the limit of the weak magnetic coupling as compared to the spin–orbit coupling, |J/λ| < 0.1. The model allows the treatment of each cobalt(II) ion in axial symmetry as an effective spin S_eff = 1/2. That causes a drastic reduction of the matrix size of the polynuclear compounds from 12ⁿ × 12ⁿ to 2ⁿ × 2ⁿ, n being the number of Co(II) ions in the complex. The main advantage of the model is to make possible the fit of the magnetic susceptibility data of those polynuclear Co(II) complexes whose high nuclearity involved intractable matrices.     

Free metal ion depletion by “good's” buffers: II. N-(2-acetamido)-2-aminoethanesulfonic acid (ACESH): Complexes with Calcium(II), Magnesium(II), Manganese(II), Cobalt(II), Zinc(II), Nickel(II), and Cooper(II)

Potentiometric, visible, and infrared studies of the complexation of N-(2-acetamido)-2-aminoethanesulfonic acid (ACESH) by Ca(II), Mg(II), Mn(II), Co(II), Zn(II), Ni(II), and Cu(II) are reported. Ca(II), Mg(II), and Mn(II) were found not to complex with ACES^?, while Co(II), Zn(II), Ni(II), and Cu(II) were found to form 2:1, ACES^? to M²⁺, complexes, and [Cu(ACES)₂] was found to undergo stepwise deprotonation of the amide groups to form [Cu(H_?1ACES)₂^2?]. Formation (affinity) constants for the various metal complexes are reported, and the probable structures of the various metal chelates in solution are discussed.     

Horse liver alcohol dehydrogenase derivatives containing nickel(II) and cobalt(lI) in the noncatalytic metal binding site

The noncatalytic zinc in horse liver alcohol dehydrogenase was selectively replaced by nickel(II). This novel species, Zn(c)₂Ni(n)₂⁴ horse liver alcohol dehydrogenase (where c denotes the catalytic and n denotes the noncatalytic site) was compared to Zn(c)₂Co(n)₂ horse liver alcohol dehydrogenase with respect to its absorption, circular dichroism and magnetic circular dichroism spectra, as well as its magnetic moment. For Zn(c)₂Co(n)₂ horse liver alcohol dehydrogenase (prepared according to refs. 1 and 2) the extinction coefficients were redetermined in the UV, visible and near-infrared region and the molar ellipticities in the range 300-800 nm. The average magnetic moment was determined by the NMR method as 4.5-5.0 B.M. The results confirm a tetrahedral structure in the zinc-cobalt enzyme. In contrast, the spectroscopic data and the zero magnetic moment support a planar geometry for the nickel(Il) bound in the noncatalytic site. Zn(c)₂Ni(n)₂ horse liver alcohol dehydrogenase is very temperature-sensitive and precipitates after short exposure to room temperature. Stored in the cold it has the same activity as the native enzyme. The results indicate that the protein is flexible in the loop region binding the noncatalytic metal ion and that it may retain catalytic activity even in a partially distorted conformation.     

Physico-chemical study of first row transition metal ions coordination compounds with N,N′-bis(2-tosylaminobenzylidene)-1,3-diaminopropanol. The crystal structure of bis-azomethine and its cobalt(II) complex

The novel Cu(II), Ni(II), Zn(II), Co(II) coordination compounds with Schiff base ligand - N,N′-bis(2-tosylaminobenzylidene)-1,3-diaminopropanol have been synthesized and studied. The structures of bis-azomethine as well as Co(II) and Zn(II) mononuclear metallochelates have been determined by X-ray analysis. The magnetic properties of all complexes were studied and interpreted in terms of HDVV theory. It was shown that exchange interaction in binuclear copper(II) complexes was affected by tosyl groups.     

Complexes of a macrocyclic ligand having both mono- and binucleating capability: binuclear Mn(II), Fe(II), Co(II), Ni(II), Zn(II) complexes

Bi-nuclear complexes of 28- atom membered macrocycles derived from 2,6-diacetyl pyridine and the amines 3,3′-diamino dipropylamine or 3,3′-diamino-N-methyl dipropylamine have been prepared by template synthesis on Ag⁺ or Pb²⁺. Template synthesis can also be accomplished, in the case of 3,3′-diamino dipropylamine, but not its N-methyl derivative, on Gp(II) metal ions, with accompanying rearrangement of the macrocycle. All the complexes produced by template synthesis can be transmetallated with the first transition series metal ions M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) to give binuclear and in some cases, mononuclear, derivatives. The binuclear complexes show no evidence of magnetic exchange interaction from magnetic susceptibility measurements in the range 93-300 K. The cyclovoltammetric behaviour of mono- and bi-nuclear Fe(II) complexes is compared.     

Electronic structure and magnetic coupling of two dinuclear trigonal bipyramidal cobalt(II) complexes

The EPR spectra of zinc-doped (bis(N-methylsalicylaldiminato)cobalt(II), (Zn, Co) SALMe, which was found to be dinuclear, and of zinc-doped bis(N,N-bis(2-(diethylamino)ethyl)-2-hydroxyethylamino-O)dicobalt(II)diperchlorate, (Zn, Co)n₃o, were recorded at liquid helium temperature and X-band frequency.The polycrystalline powder spectra of (Zn, Co)SALMe were interpreted within an effective S = 1/2 spin hamiltonian formalism with g₁ = 1.8, g₂ = 2.7, g₃ = 6.2, while those of (Zn, Co)n₃o showed only one band at G= 6.9. The single crystal spectra for the latter yielded g₁ = 0.31(4), g₂ = 0.84(4), g₃ = 6.86(2). The electronic structure of the complexes was calculated using the AOM, and the lowest Kramers doublet for CoSALMe was found to be ±1/2 while a ±3/2 doublet was found for Con₃o. The temperature dependence of the magnetic susceptibility of CoSALMe was measured between 295 and 4.2 K. The data were fitted with two different methods which either took into account or neglected the zero-field splitting of single ions. The coupling was found to be antiferromagnetic with J = 9.8(2) cm^-1 (J is defined through the hamiltonian = JS₁·S₂). The extent of the magnetic interaction between the metal ions for both the complexes was discussed on the basis of a structural analysis.     

Transition-metal(II) thiocyanate coordination compounds containing 4-allyl-1,2,4-triazole. Structure and magnetic properties.

The synthesis and characterisation of a series of dinuclear and polynuclear coordination compounds with 4-allyl-1,2,4-triazole are described. Dinuclear compounds were obtained for Mn(II) and Fe(II) with composition [M₂(Altrz)₅(NCS)₄], and for Co(II) and Ni(II) with composition [M₂(Altrz)₄(H₂O)(NCS)₄](H₂O)₂. The crystal structure of [Co₂(Altrz)₄(H₂O)(NCS)₄](H₂O)₂ was solved at room temperature. It crystallizes in the monoclinic space group P2₁/n. The lattice constants are a = 18.033(3) Å, b = 13.611(2) Å, c = 15.619(3) Å, β = 92.04(2)° Z = 4. One cobalt ion has an octahedrally arranged donor set of ligands consisting of three vicinal nitrogens of 1,2-bridging triazoles (CoN = 2.14–2.15 Å), one terminal triazole nitrogen (CoN = 2.12 Å) and two N-bonded NCS anions (CON = 2.08 Å). The other Co(II) ion has the same geometry, but the terminal triazole ligand is replaced by H₂O (CoO = 2.15 Å). The crystal structure is stabilised by hydrogen bonding through H₂O molecules, S-atoms of the NCS anions and the lone-pair electron of the monodentate triazole. The magnetic exchange in the Mn, Co and Ni compounds is antiferromagnetic with J-values of ?0.4 cm^?1, ?10.9 cm^?1 and ?8.7 cm^?1 respectively. The Co compound was interpreted in terms of an Ising model. For [Zn₂(Altrz)₅(NCS)₂]∞[Zn(NCS)₄], [Cu₂(Altrz)₃(NCS)₄]∞ and [Cd₂(Altrz)₃(NCS)₄]∞ chain structures are proposed. In the Cu compound thiocyanates appear to be present, bridging via the nitrogen atom, as deduced from the IR spectrum.     

Stability studies in relation to IR data of some schiff base complexes of transition metals and their biological and pharmacological studies

Schiff bases derived from salicylaldehyde and 2-substituted anilines and their Cu(II), Ni(II) and Co(II) complexes have been synthesized and characterized by their elemental analysis, TGA, IR and electronic spectral studies, molar conductance and magnetic susceptibility measurements. The mode of bonding between Cu(II), Ni(II) and Co(Il) and Schiff bases has been studied by IR spectrophotometry. The shift in the band positions of the groups involved in coordination has been utilized to estimate the metal- nitrogen bond lengths. The results obtained are in good agreement with the values of metal-nitrogen modes and ligand-field splitting energy (10 Dq). The antimicrobial activities of the synthesized ligands and their metal complexes have been determined on Gram-positive (Staphylococcus aureus), Gram- negative (Escherichia coli) bacteria and on fungi like Aspergillus niger, Aspergillus nidulense and Candida albicans. The antimicrobial activity of the organic ligands increased several folds on chelation as compared to the ligand molecule alone. However, their anti-inflammatory activity showed a different pattern; the activity of some ligands was more than their respective metal chelates. It is interesting to note that only cobalt complexes exhibited anti-inflammatory activity.     

Synthesis, structure, and magnetism of a binuclear Co(II) complex of a potentially bis-tridentate verdazyl radical ligand

The synthesis, structure, and magnetic properties of a dinuclear Co(II) complex of a tridentate verdazyl radical are presented. The reaction of a tetrazane containing a 4,6-bis(2-pyridyl)-pyrimid-2-yl substituent with cobalt chloride hexahydrate in aerated solution leads to in situ oxidation of the tetrazane to a verdazyl radical which is coordinated to Co(II) in a tridentate manner. The second tridentate coordination site of the verdazyl remains vacant. The crystal structure reveals the complex to be dimeric, with the cobalt ions linked by two bridging chlorides. The structure of Co₂Cl₂ core is highly asymmetric, with two short (2.3317 Å) and two long (2.744 Å) Co-Cl bonds. There are relatively short intermolecular contacts between coordinated verdazyl radicals in the solid state. Magnetic susceptibility data from 2 to 300 K suggest intramolecular ferromagnetic interactions, and modeling of the high-temperature data produced a best fit with J_Co-verdazyl of +20 cm⁻¹.     

Synthesis,characterization and antitumour properties of some metal(II) complexes of 2-pyridinecarboxaldehyde 2′-pyridylhydrazone and related compounds

Metal complexes of 2-pyridinecarboxaldehyde 2′-pyridylhydrazone (PCPH) and related compounds with manganese(II), iron(II), cobalt(II), nickel(Il), copper(II), zinc(II) and platinum(II) were synthesized and characterized by magnetic susceptibility measurements down to liquid nitrogen temperature and also by electronic, infrared, electron spin resonance and Mössbauer spectra. All the metal(II) complexes appeared to be monomeric, high-spin, five-coordinate (square-pyramidal) (X = Cl⁻ or OAc⁻), except for Ni(PCPH)Cl₂ which is polymeric, high-spin, six-coordinate. Each ligand behaved as a tridentate NNN donor, via the pyridine nitrogen, azomethine nitrogen, and pyridine or quinoline nitrogen. One of the most active agents of this series, Cu(PCPH)Cl₂, showed antitumour activity against a variety of transplanted tumours, including Sarcoma 180, Ehrlich carcinoma and L1210 leukaemia sensitive to α(N)-heterocyclic carboxaldehyde thiosemicarbazones. This agent caused inhibition of ³H-thymidine and ³H-uridine incorporation into DNA and RNA, respectively, of Sarcoma 180 ascites cells; protein biosynthesis was relatively insensitive to the action of this agent.