Syntheses and crystal structures of mono-, di- and trinuclear cobalt complexes of a salen type ligand

Three cobalt complexes containing the salen type ligand, bis(salicylidene)-meso-1,2-diphenylethylenediaminato (mdpSal²⁻), are reported. The complexes differ in nuclearity and include the mononuclear, Co(mdpSal) (1), which contains a Co(II) metal center bound to one mdpSal⁻² ligand frame in a square planar geometry. The second complex is the dinuclear [Co(mdpSal)Cl]₂ (2) in which both cobalt ions have been oxidized to the +3 oxidation state. The overall geometry of complex 2 is an edge-sharing bioctahedron with the coordination sphere around each cobalt metal center consisting of one mdpSal⁻² ligand and one Cl⁻ ion. The shared edge between the Co(III) ions contains two bridging phenolate groups, one from each ligand frame. Complex 3 is a linear, mixed valence, trinuclear species, [Co(mdpSal)(OAc)(μ-OAc)]₂Co, with the oxidation states of the metal centers assigned as Co(III)-Co(II)-Co(III). The terminal Co(III) centers are equivalent with the central Co(II) lying on the inversion center of the molecule. Each cobalt ion in 3 adopts an octahedral geometry with the terminal Co(III) ions being bound to one mdpSal²⁻ ligand each. All phenolate groups bridge to the central Co(II). The coordination sphere about each metal center in the trinuclear complex is completed by four acetate groups, two of which bind in a μ-fashion bridging from the terminal Co(III) metal centers to the central Co(II). The complexes have been characterized by X-ray crystallography as well as UV-Vis and IR spectroscopy.     

The effect of binding of cobalt(III)--nucleotide complexes on the kinetic properties of adenosine triphosphatase activity in coupling factor 1 from chloroplasts.

Co(III)-ATP and Co(III)-ADP as well as the parent complexes containing phenanthroline as an additional ligand were found to inhibit ATPase activity competitively in coupling factor 1 from chloroplasts. The K_i values were at the micromolar range and were found to decrease with time of preincubation of the enzyme with the Co(III) complexes. Co(III)-phenanthroline-ATP was found to bind to the enzyme at two sites with dissociation constants of 1 and 3 μm. The labeling as well as the inhibition was completely reversed by dithiothrietol. In addition, the complexes caused a time-dependent release of enzyme-bound Mn(II) ions, thus labeling the metal binding site. The results were interpreted with regard to the mechanism of ATPase activity in coupling factor 1.     

Synthesis, characterization and antibacterial properties of some trivalent metal complexes with [(2-hydroxy-1-naphthaldehyde)-3-isatin]-bishydrazone

Complexes of manganese(III), iron(III) and cobalt(III) with a bishydrazone, formed by condensation of isatin monohydrazone with 2-hydroxy-1-naphthaldehyde, have been synthesized. The spectral data reveal that the ligand acts as monobasic tridentate, coordinating through the deprotonated naphtholate oxygen, azomethine nitrogen, and carbonyl oxygen. Molar conductance values adequately support the electrolytic nature of the complexes. On the basis of the above observations the complexes have been formulated as [M(NIB)2]X where M = Mn(III), Fe(III) or Co(III); X = Cl-, NO3(-); or OAc-; HNIB = [(2-hydroxy-1-naphthaldehyde)-3-isatin]-bishydrazone. Based on electronic spectral data and magnetic moment values, an octahedral geometry has been proposed. The iron(III) complex has been subjected to thermal decomposition studies. The ligand and the metal complexes have been screened for their antibacterial activity and it has been observed that the complexes are more potent bactericides than the ligand.     

Demonstration of nitrogen coordination in metal--bleomycin complexes by electron spin--echo envelope spectroscopy

We have studied the Cu(II), Co(II), and Fe(III) complexes of the antineoplastic drug bleomycin by using electron spin--echo envelope spectroscopy. For all three complexes, nitrogen coordination of the metal ions is demonstrated. For the Cu(II)-- and Co(II)--drug complexes, we have been able to identify imidazole as a metal ligand.     

Metal coordination core of bleomycin : comparison of metal complexes between bleomycin and its biosynthetic intermediate.

On the basis of electron spin resonance results, the 1:1 Cu(II), Co(II), Co(II)-O₂, and Ni(III) complexes of bleomycin(BLM) have been compared with the corresponding metal complexes of its biosynthetic intermediate(P-3A). The present study suggests that (1) P-3A is an useful ligand for the clarification of metal-binding sites of BLM; (2) the secondary amine, pyrimidine ring nitrogen, deprotonated peptide nitrogen of histidine residue, and histidine imidazole groups as planar ligand donors, and the α-amino group as axial donor, are substantially important for metal-coordination of BLM; and (3) the sugar and bithiazole portions of BLM probably contribute to stabilization of Co(II)-O₂ adduct complex and axial sixth coordination of Cu(II) and Ni(III) complexes.     

Spectral and redox studies on mixed ligand complexes of cobalt(III) phenanthroline/bipyridyl and benzoylhydrazones, their DNA binding and antimicrobial activity

Cobalt(III) complexes of the type [Co(N-N)2L](ClO4)2.H2O [where L=anionic form of para-substituted benzaldehyde-benzoylhydrazone (BHBX-); X=H, Me, OMe, OH, Cl or NO2; N-N=2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen)] have been synthesized and characterized through UV-Vis, IR, NMR and electrochemical studies. The IR spectral frequencies support the mode of coordination of BHBX to the metal through the imino nitrogen and enolic oxygen atoms. The electronic absorption spectra exhibit metal to ligand charge transfer (MLCT) transition around 450 nm together with intraligand (IL) bands that are comparable to that of [Co(phen/bpy)3]3+. In acetonitrile solution these complexes show two well defined redox couples corresponding to Co(III/II) and Co(II/I) processes. Binding of these complexes with herring sperm DNA have been investigated by spectroscopic and voltammetric methods. The lower binding constant values of these complexes with respect to the [Co(phen/bpy)3]3+ are ascribed to the polar interaction of the substituted benzoylhydrazone moiety with the sugar-phosphate backbone of the DNA. The UV spectrum shows reasonable hypochromism with slight (2-4 nm) red shift, while the cyclic voltammogram shows decrease in current intensity along with a very small shift in the formal potential of the Co(III/II) redox couple. These experimental results indicate that phen mixed ligand complexes bind to DNA through an intercalative mode more effectively than their bpy counterparts. These complexes are also found to have good antimicrobial activity.     

Kinetic and magnetic properties of cobalt(III) ion in the active site of carbonic anhydrase.

Cobalt(III)bovine carbonic anhydrase B was prepared by the oxidation of the cobalt(II) enzyme with hydrogen peroxide and was purified by affinity chromatography. The oxidation reaction is inhibited by specific inhibitors of carbonic anhydrase. The inhibition is explained by the fact that the Co(II)-enzyme . inhibitor complex cannot be directly oxidized by hydrogen peroxide, but has to dissociate to give free Co(II) enzyme which is then oxidized. The Co(III) ion in Co(III) carbonic anhydrase cannot be directly substituted by zinc ions. It can be reduced by either dithionite or BH-4 ions to give, first, their complexes with the Co(II) enzyme, and upon their removal, a fully active Co(II) enzyme. Cyanide and azide bind to cobalt(III) carbonic anhydrase with similar rate constants of 0.060 +/- 0.005 and 0.070 +/- 0.007 M-1 S-1 respectively. These rates are faster than those found for Co(III) inorganic complexes. The Co(III) ion in both Co(III) carbonic anhydrase and Co(III) carboxypeptidase A was found to be diamagnetic, indicating a near octahedral symmetry.     

Cobalt(II), nickel(II), copper(II) and zinc(II) complexes with an open-chain pentadentate nitrogen ligand

The open-chain, potentially, pentadentate, ligan 1,11-bis(dimethylamino)-3,6,9-trimethyl-3,6,9,-triazaundecane (Me₇tetren) forms a series of metal complexes having the general formula [M(Me₇tetren)]Y₂ (Y = 1, M = Co, Ni; Y = ClO₄, M = Co, Ni, Cu, Zn). On the basis of their physical properties, it is suggested that all these compounds contains isostructural five-coordinate [M(Me₇tetren)]²⁺ cations, the ligand acting as pentadentate. These complexes react in solution with thiocyanate ion to give mono- and, with exception of copper(II), di-thiocyanato five- and six-co-ordinate derivatives. Mono-thiocyanato derivatives of cobalt(II), nickel(II) and zinc(II) have been isolated as tetraphenylborate salts. Cobalt(II) and nickel (II) di-thiocyanato derivatives have been also isolated. Results are discussed in terms of the steric requirements of the ligand and electronic properties of the metal ions.     

Oxidative addition of quinones to planar cobalt(II) dithiolato,dithioacetylacetonato and Schiff-base complexes

The reactivity of ortho- and para-quinones with various four-coordinated planar Co(II) complexes was investigated. The o-quinones add oxidatively, producing Co(III) complexes containing chelated o-semiquinone radical-anions. No coordination of the fifth ligand in the axial position is involved in these reactions. The reaction between o-quinones and Co(II) dithiolates represents the first known example of oxidative addition to Co(II) dithiolato complexes. All observed oxidative additions are reversible; the position of the equilibrium depends strongly on the nature of the equatorial ligand. The extent of radical adduct formation decreases in the order: dithioacetylacetonate > Schiff bases > dithiolates. When redox potentials of the reacting species are changed in a way that makes simple electron transfer between Co(II) complexes and quinones thermodynamically possible, the reduction of quinones to free semiquinone radical-anions becomes competitive with the oxidative addition. In the case of p-quinones, only electron transfer is observed if the thermodynamic conditions are met. The structural factors determining quinone reactivity are briefly discussed.     

Antimicrobial, spectral, magnetic and thermal studies of Cu(II), Ni(II), Co(II), UO(2)(VI) and Fe(III) complexes of the Schiff base derived from oxalylhydrazide

The Schiff base ligand, oxalic bis[(2-hydroxybenzylidene)hydrazide], H(2)L, and its Cu(II), Ni(II), Co(II), UO(2)(VI) and Fe(III) complexes were prepared and tested as antibacterial agents. The Schiff base acts as a dibasic tetra- or hexadentate ligand with metal cations in molar ratio 1:1 or 2:1 (M:L) to yield either mono- or binuclear complexes, respectively. The ligand and its metal complexes were characterized by elemental analyses, IR, (1)H NMR, Mass, and UV-Visible spectra and the magnetic moments and electrical conductance of the complexes were also determined. For binuclear complexes, the magnetic moments are quite low compared to the calculated value for two metal ions complexes and this shows antiferromagnetic interactions between the two adjacent metal ions. The ligand and its metal complexes were tested against a Gram + ve bacteria (Staphylococcus aureus), a Gram -ve bacteria (Escherichia coli), and a fungi (Candida albicans). The tested compounds exhibited high antibacterial activities.     

Optimization of the auxiliary ligand shell of Cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs

A potential approach for activating prodrugs in hypoxic regions of tumors is to use ionizing radiation, rather than bioreductive enzymes, to effect reduction. This study investigates radiolytic release of 8-hydroxyquinoline (8-HQ), as a model for hydroxyaza-chloromethylbenzindoline DNA minor groove alkylators, from Co(III) complexes under hypoxia. 8-HQ release, measured by HPLC, showed higher efficiency (one-electron stoichiometry) when the auxiliary ligand was a tetraazamacrocycle [e.g. 1,4,7,10-tetraazacyclododecane (cyclen)] rather than a triazamacrocycle [1,4,7-triazacyclononane (TACN)]. These complexes differ from the bioreductive cobalt complex SN 24771 in that their reduction provides stable cobalt-containing products rather than free (aquated) Co(2+). Radiolytic release of 8-HQ from Co(cyclen)(8-HQ) and Co(TACN)(CN)(8-HQ) was also demonstrated in deoxygenated human plasma, selectively in the absence of oxygen, again with higher efficiency for the cyclen system. The cobalt complexes were >1000-fold less potent than free 8-HQ as inhibitors of cell proliferation and were metabolically stable in aerobic and hypoxic cell cultures. Investigation of cell uptake of total cobalt, by inductively coupled plasma mass spectrometry, showed that these complexes enter cells but do not accumulate to the high concentrations seen with SN 24771. The results demonstrate the feasibility of masking the cytotoxicity of hydroxyquinoline-based cytotoxins as Co(III) complexes and demonstrate the utility of cyclen-based auxiliary ligands for optimizing radiolytic activation of these novel prodrugs under hypoxia.     

Synthesis and characterization of the cobalt(III) complexes of two pendant-arm cross-bridged cyclams

The cobalt(III) complexes of 4,11-diacetato-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), [Co(1)]PF₆, and 4,11-diacetamido-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2), [Co(2)][PF₆]₃, have been synthesized and characterized. The crystal structure of [Co(1)]PF₆ consists of an octahedral cobalt(III) cation coordinated to all four ligand nitrogen donors in the macrobicycle’s cavity, as well as to the deprotonated carboxylate oxygen atoms of both pendant arms. Analytical and spectroscopic data indicates that the ligand in [Co(2)][PF₆]₃ is not deprotonated, suggesting coordination through the amide carbonyl oxygens. Study of the electronic spectra of these novel complexes and comparison with data from related cobalt(III) complexes characterizes the ligands as strong field with Δ₀=24,040 and Δ₀=24,250 cm⁻¹ for 1 and 2, respectively. Cyclic voltammograms were obtained for both complexes with large variations observed due to the differences in ligand charge and coordination.     

Azide promotion of alkane oxidations catalyzed by metal complexes in solution

The oxidation of light alkanes catalyzed by metal complexes in solution is promoted by Group 1 metal azides. Yields of oxygenated reaction products are greatly enhanced when catalytic amounts of azides are added to the reaction mixture. The addition of sodium azide to oxidations catalyzed by transition metal acetylacetonates, heteropolyacids, polyoxometallates, phthalocyanines, bis-(pyridylimino)isoindolines, porphyrins and Schiff bases significantly enhances rates of low-temperature catalytic oxidation reactions in the liquid phase. Earlier work showed that Cr(III), Mn(III), Fe(III) and Co(III) complexes of electron-deficient macrocyclic complexes exhibited remarkable catalytic activity for oxidizing light alkanes. Such complexes bearing axial azide ligands were far more active than their axial chloride or acelate counterparts.     

Molecular docking,PASS analysis,bioactivity score prediction,synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes

2-Butanone thiosemicarbazone ligand was prepared by condensation reaction between thiosemicarbazide and butanone. The ligand was characterized by ¹H NMR, ¹³C NMR, FT-IR, mass spectrometry and UV spectroscopic studies. Docking studies were performed to study inhibitory action against topoisomerase II (Topo II) and ribonucleoside diphosphate reductase (RR) enzymes. Inhibition constants (K _i ) of the ligand were 437.87 and 327.4 μM for the two enzymes, respectively. The ligand was tested for its potential anticancer activity against two cancer cell lines MDA-MB-231 and A549 using MTT assay and was found to exhibit good activity at higher doses with an IC₅₀ = 80 μM against human breast cancer cell line MDA-MB-231. On the other hand, no significant activity was obtained against the lung carcinoma cell line A549. Antibacterial activity of the ligand was tested against Staphylococcus aureus and E. coli using the disc diffusion method. Ligand did not exhibit any significant antibacterial activity. Four complexes of Co(III), Fe(II), Cu(II), and Zn(II) were prepared with the ligand and characterized by various spectroscopic studies. Low molar conductance values were obtained for all complexes displaying non-electrolyte nature except in Co(III) complex. As expected, complexation with metal ions significantly increased the cytotoxicity of the ligand against the tested cell lines viz. IC₅₀ values of <20 μM for Co, Fe, and Zn complexes and approx. 80 μM against MDA cells versus IC₅₀ value of <20 μM for Co and Cu complexes and that of 30 and 50 μM for Fe and Zn complexes, respectively, against A549 cells. The Cu complex was found to be active against E. coli and S. aureus with MIC values in the range of 6–10 mg/mL. Other than Cu, only Co complex was found to possess antibacterial activity with MIC values of 5–10 mg/mL when tested against S. aureus. Bioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis also depicted the drug-like nature of ligand and complexes.     

Binding and oxidative cleavage studies of DNA by mixed ligand Co(III) and Ni(II) complexes of quinolo [3,2-b]benzodiazapine and 1,10-phenanthroline

Two mixed ligand complexes of the type [M(phen)(2)(qbdp)](PF(6))n.xH(2)O where M = Co(III) and Ni(II), qbdp = quinolo[3,2-b] benzodiazepine and phen = 1,10-phenanthroline, n = 3 or 2, x = 2 or 3 have been synthesized and characterized by employing analytical and spectral methods. The DNA binding property of the complexes with calf thymus-DNA has been investigated by using absorption spectra, viscosity measurements as well as thermal denaturation studies. The absorption spectral results indicate that the Co(III) and Ni(II) complexes intercalate between the base pairs of the DNA tightly with intrinsic DNA binding constant of 6.4 x 10(4) and 4.8 x 10(4) M(-1) in Tris HCl buffer containing 50 mM NaCl, respectively. The large enhancement in the relative viscosity of DNA on binding to the quinolo [3,2-b] benzodiazepine supports the proposed DNA binding modes. The complexes on reaction with super coiled (SC) DNA shows nuclease activity.     

In-vitro antibacterial, antifungal activity of some transition metal complexes of thiosemicarbazone Schiff base (HL) derived from N4-(7'-chloroquinolin-4'-ylamino) thiosemicarbazide

The synthetic, spectroscopic, and biological studies of Cu(II), Ni(II), Zn(II), Co(II), Mn(II), Fe(III) and Cr(III) complexes of N(4)-(7'-chloroquinolin-4'-ylamino)-N(1)-(2-hydroxy-benzylidene)thiosemicarbazone (HL) obtained by the reaction of N(4)-(7'-chloroquinolin-4'-ylamino)thiosemicarbazide with 2-hydroxybenzaldehyde. The structures of the complexes were determined on the basis of the elemental analyses, spectroscopic data (IR, electronic, (1)H and (13)C NMR and Mass spectra) along with magnetic susceptibility measurements, molar conductivity and thermogravimetric analyses. Electrical conductance measurement revealed the non-electrolytic nature of the complexes. The resulting colored products are mononuclear in nature. On the basis of the above studies, only one ligand was suggested to be coordinated to each metal atom by thione sulfur, azomethine nitrogen and phenolic oxygen to form mononuclear complexes in which the thiosemicarbazone behaves as a monobasic tridendate ligand. The ligand and its metal complexes were tested against Gram + ve bacteria (Staphylococcus aureus), Gram - ve bacteria (Escherichia coli), fungi (Candida albicans) and (Fusarium solani). The tested compounds exhibited significant activity.     

Shewanella putrefaciens produces an Fe(III)-solubilizing organic ligand during anaerobic respiration on insoluble Fe(III) oxides

The mechanism of Fe(III) reduction was investigated using voltammetric techniques in anaerobic incubations of Shewanella putrefaciens strain 200 supplemented with Fe(III) citrate or a suite of Fe(III) oxides as terminal electron acceptor. Results indicate that organic complexes of Fe(III) are produced during the reduction of Fe(III) at rates that correlate with the reactivity of the Fe(III) phase and bacterial cell density. Anaerobic Fe(III) solubilization activity is detected with either Fe(III) oxides or Fe(III) citrate, suggesting that the organic ligand produced is strong enough to destabilize Fe(III) from soluble or solid Fe(III) substrates. Results also demonstrate that Fe(III) oxide dissolution is not controlled by the intrinsic chemical reactivity of the Fe(III) oxides. Instead, the chemical reaction between the endogenous organic ligand is only affected by the number of reactive surface sites available to S. putrefaciens. This report describes the first application of voltammetric techniques to demonstrate production of soluble organic-Fe(III) complexes by any Fe(III)-reducing microorganism and is the first report of a Fe(III)-solubilizing ligand generated by a metal-reducing member of the genus Shewanella.     

Cellular up-regulation of Nedd4 family interacting protein 1 (Ndfip1) using low levels of bioactive cobalt complexes

The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.     

Biological activity of complexes derived from pyridine-2-carbaldehyde thiosemicarbazone. Structure of

Biological studies on [Fe(L)2](NO3).0.5H2O (1), [Fe(L)2][PF6] (2), [Co(L)2](NCS) (3), [Ni(HL)2]Cl2.3H2O (4) and Cu(L)(NO3) (5), where HL=C7H8N4S, pyridine-2-carbaldehyde thiosemicarbazone, have been carried out. The crystal structure of compound 3 has been solved. It consists of discrete monomeric cationic entities containing cobalt(III) ions in a distorted octahedral environment. The metal ion is bonded to one sulfur and two nitrogen atoms of each thiosemicarbazone molecule. The thiocyanate molecules act as counterions. The copper(II) and iron(III) complexes react with reduced glutathione and 2-mercaptoethanol. The reaction of compound 1 with the above thiols causes the reduction of the metal ion and bis(thiosemicarbazonato)iron(II) species are obtained. The redox activity, and in particular the reaction with cell thiols, seems to be related to the cytotoxicity of these complexes against Friend erithroleukemia cells and melanoma B16F10 cells.     

Antimicrobial,spectral, magnetic and thermal studies of Cu(II), Ni(II), Co(II), UO2(VI) and Fe(III) complexes of the Schiff base derived from oxalylhydrazide

The Schiff base ligand, oxalic bis[(2-hydroxybenzylidene)hydrazide], H₂L, and its Cu(II), Ni(II), Co(II), UO₂(VI) and Fe(III) complexes were prepared and tested as antibacterial agents. The Schiff base acts as a dibasic tetra- or hexadentate ligand with metal cations in molar ratio 1:1 or 2:1 (M:L) to yield either mono- or binuclear complexes, respectively. The ligand and its metal complexes were characterized by elemental analyses, IR, ¹H NMR, Mass, and UV-Visible spectra and the magnetic moments and electrical conductance of the complexes were also determined. For binuclear complexes, the magnetic moments are quite low compared to the calculated value for two metal ions complexes and this shows antiferromagnetic interactions between the two adjacent metal ions. The ligand and its metal complexes were tested against a Gram + ve bacteria (Staphylococcus aureus), a Gram -ve bacteria (Escherichia coli), and a fungi (Candida albicans). The tested compounds exhibited high antibacterial activities.