Acyclic and macrocyclic schiff base complexes of lanthanides and actinides

The work reviewed here is the result of a collaborative project designed to explore the interaction of lanthanides and actinides with acyclic and macrocyclic Schiff base ligands. The ligands are penta- and hexa-dentate in character and have present arrays of donors drawn from oxygen, nitrogen and sulphur atoms. The acyclic ligands are capable of allowing binuclear incorporation to occur; this feature was included in the study as is the area of selective metal extraction. A single ligand capable of removing two cations simultaneously would have cost benefit advantage over a ligand capable only of removing a single cation.     

Binding of sulfonamide and acetamide to the active-site Zn2+ in carbonic anhydrase: a theoretical study

Self-consistent field molecular orbital (SCF MO) calculations at both 4-31G and STO-3G levels have been used to examine the binding conformations of sulfonamide and acetamide compounds to the active site of carbonic anhydrase. The results are as follows: (1) sulfonamide binds to the Zn2+ ion in its deprotonated form through the sulfonamide nitrogen to the fourth coordination site of the metal ion; (2) acetamide as neutral species binds to the basic form of the enzyme through the carbonyl oxygen to the fifth coordination site of the metal ion; and (3) the acetamidate ion binds to the acid form of the enzyme through the amide nitrogen to form a tetracoordinated metal complex with three histidine ligands. Analysis of the effects of individual active-site residues on the binding conformations of these inhibitors suggests that metal alone favors bidentate coordination of sulfonamidate and acetamidate complexes and that electron donation from three histidine ligands to the metal ion determines the formation of a tetracoordinated metal complex, which is further stabilized by the presence of Thr 199, as it receives one hydrogen bond from the sulfonamide NH- or from the acetamide NH- and donates a backbone NH hydrogen bond to a sulfonamide oxygen. The calculated binding conformation of sulfonamide and the hydrogen-bonding interactions between sulfonamide and the enzyme are consistent with the X-ray diffraction study of the AMSulf-HCA II complex. However, no X-ray structures are available for amide-HCA II complexes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metal ligands in micronutrient acquisition and homeostasis

Acquisition and homeostasis of micronutrients such as iron (Fe) and zinc (Zn) pose specific challenges. Poor solubility and high reactivity require controlled synthesis and supply of ligands to complex these metals extracellularly and intracellularly. Cytosolic labile pools represent only a minute fraction of the total cellular content. Several low‐molecular‐weight ligands are known in plants, including sulfur ligands (cysteine and peptides), nitrogen/oxygen ligands (S‐adenosyl‐l ‐methionine‐derived molecules and histidine), and oxygen ligands (phenolics and organic acids). Some ligands are secreted into the extracellular space and influence the phytoavailability of metal ions. A second principal function is the intracellular buffering of micronutrients as well as the facilitation of long‐distance transport in xylem and phloem. Furthermore, low‐molecular‐weight ligands are involved in the storage of metals, predominantly in vacuoles. A detailed molecular understanding is hampered by technical limitations, in particular the difficulty to detect and quantify cellular metal–ligand complexes. More, but still too little, is known about ligand synthesis and the transport across membranes, either with or without a complexed metal. Metal ligands have an immediate impact on human well‐being. Engineering metal ligand synthesis and distribution in crops has tremendous potential to improve the nutritional quality of food and to tackle major human health risks.     

Model complexes for amavadine,a vanadium natural product

Amavadine is a vanadium natural product from the mushroom Amanita muscaria. Earlier reports have characterized the compound as a vanadyl (VO²⁺) complex with two N-hydroxy-αα-iminodipropionic acid ligands, but no hypothesis as to its function has yet been put forward. We report here the synthesis, isolation, and properties of bis(iminodiacetato)oxovanadium(IV) and bis(αα-iminodipropionato)oxovanadium(IV). The complex bis(ββ-iminodipropionato)oxovanadium(IV) has been prepared in solution. These complexes serve as models for Amavadine. The structures of the models are analogous to that of Amavadine, with two bidentate, singly charged ligands bonding through one oxygen and one nitrogen atom. The visible spectra suggest the possibility of 1:1 complexes in solution in addition to the 2:1 ligand to metal complexes. Preliminary electrochemical data suggest reversible V(IV) ? V(III) couples.     

Spectroscopic and structural analyses of the copper(II) 2-D coordination polymer {[Cu2(BPP)4(NCS)4]}n (BPP = 1,3-bis(4-pyridyl)propane) comprising interpenetrated layers of (4, 4) topology

The synthesis and structural characterization of the 2-D Cu(II) coordination polymer namely {[Cu₂(BPP)₄(NCS)₄]}_n, where BPP is the nitrogen ligand 1,3-bis(4-pyridyl)propane, are described. Single crystal diffraction analysis shows that the asymmetric unit consists on two crystallographically independent Cu(II) ions that adopt a distorted octahedral geometry. Each Cu(II) center is coordinated by four nitrogen atoms from different BPP ligands and by other two nitrogen atoms from isothiocyanate groups. The BPP ligands link the metal centers generating an undulated two-dimensional net of (4, 4) topology. Two sets of two-dimensional sheets interlock each other in the same plane, giving rise to a twofold parallel interpenetrating network. EPR spectra indicate no magnetic coupling of the two individual Cu²⁺ centers.     

Synthesis, molecular structure determination, and antitumor activity of platinum(II) and palladium(II) complexes of 2-substituted benzimidazole

The complexes of 2-aminomethyl benzimidazole, 2-(beta-aminoethyl)benzimidazole, and 2-(alpha-aminoethy-l)benzimidazole with Pt(II) and Pd(II) have been prepared. The molecular structure of the free ligands and their complexes were studied by IR and 1H NMR. It was concluded that the substituted benzimidazole derivatives behave as bidentate ligands, being bound to the metal atoms via the nitrogen of the -N = group and the amino group of the side chain of the benzimidazole ring. The metal complexes were tested for antineoplastic activity both in cultures of neoplastic cells (MEL-745, K-562, Colon 205, IMP-32, SK-N-SH) and in vivo in rodents bearing L-1210 leukemia. The antiproliferative activity of these agents was compared to that of cis-platin.     

Binding of ligands to the catalytic zinc ion in horse liver alcohol dehydrogenase

The affinity of nitrogen and sulfur ligands for the catalytic zinc ion in horse liver alcohol dehydrogenase has been investigated by their influence on the affinity labeling reaction with iodoacetate. All the nitrogen compounds including ammonia, a primary and a secondary amine, and heterocycles containing a pyridine-type nitrogen with the exception of 2,2-dipyridyl were found to activate the affinity labeling reaction. Activation results from inner-sphere ligand coordination to the catalytic zinc ion. Closely related pyridine compounds gave a regular increase in affinity for the enzyme with increasing basicity, as expected for coordination to a metal ion. The sulfur compounds penicillamine and mercaptoethanol also activated the affinity labeling reaction, but dimercaptopropanol bound very tightly as a bidentate inhibited the reaction. The anions hydrosulfide, diethyldithiocarbamate, and cyanide coordinated to the catalytic zinc ion, whereas azide, thiocyanate, tetrazole, and iodide complexed the anion-binding site. The anionic metal ligands increased the rate of inactivation of the enzyme with iodoacetamide by binding to the catalytic zinc ion, while the binding of iodoacetate to the anion-binding site was prevented.     

Structural study of few p-phenylenediacetate complexes of Mn, Cu, Zn and Cd

Different metal carboxylate complexes are prepared by reactions of manganese (+2) acetate, copper (+2) acetate, zinc (+2) acetate and cadmium (+2) acetate with p-phenylenediacetic acid under ambient condition with or without a nitrogen donor ligands and each of them are characterized by conventional spectroscopic techniques along with crystallography.     

Synthesis of substituted indazoles and their corresponding tris(indazolyl)borate tripodal ligands as key building blocks for molecular motors

The synthesis of functionalized indazoles at the 6-position of the indazole ring is developed. Such precursors give access to tris(indazolyl)borate ligands derived from the scorpionate ligands of Trofimenko. These tripodal ligands are truly bifunctional since they can coordinate a metal via the nitrogen centers of the indazolyl rings and be anchored on surfaces on the opposite side through their 6-functionalizations. Three pendant ester or thioether groups were selected to anchor metallic complexes onto, respectively, an oxide or a metallic surface in view of near-field microscopy experiments. These building blocks have been subsequently used as stator in a family of single molecular rotary motors. The architecture of such compounds is centered around half-sandwich complexes of the family of pentaphenylcyclopentadienyl hydrotris(indazolyl)borate ruthenium (II).     

Transition metal complexes of terminally protected peptides containing histidyl residues

Histidine-containing peptide fragments of prion protein are efficient ligands to bind various transition metal ions and they have high selectivity in metal binding. The metal ion affinity follows the order: Pd(II)>Cu(II)>Ni(II)Zn(II)>Cd(II) approximately Co(II)>Mn(II). The high selectivity of metal binding is connected to the involvement of both imidazole and amide nitrogen atoms in metal binding for Pd(II), Cu(II) and Ni(II), while only the monodentate N(im)-coordination is possible with the other metal ions. The stoichiometry and binding mode of palladium(II) complexes show great variety depending on the metal ion to ligand ratio, pH and especially the presence of coordinating donor atoms in the side chains of peptide fragments. It is also clear from our data that the peptide fragments containing histidine outside the octarepeat (His96, His111 and His187) are more efficient ligands than the monomer peptide fragments of the octarepeat domain.     

Escherichia coli primase zinc is sensitive to substrate and cofactor binding.

The ligation state of the single zinc site in primase from Escherichia coli changes when various substrates and cofactors are added alone or in combination as determined by X-ray absorption spectroscopy. X-ray absorption spectroscopy (XAS) provides information about the local structure (approximately 5 A) of atoms surrounding the metal and has been widely used to characterize metalloproteins. The zinc site in native primase and in primase bound to low (30 mM) magnesium acetate was found to be tetrahedrally ligated by three sulfurs at an average distance of 2.36 +/- 0.02 A and one histidine nitrogen located at a distance of 2.15 +/- 0.03 A. When ATP, ATP and (dT)17, or ATP, low magnesium acetate and (dT)17 was added to primase, one (or two) additional nitrogen/oxygen ligands were coordinated to the zinc together with the histidine nitrogen at an average distance of 2.15 +/- 0.03 A. These additional ligands are likely from adjacent phosphates from ATP. Another structure was observed for the primase-(dT)17 complex in which an additional nitrogen/oxygen ligand likely from the phosphate backbone together with the histidine nitrogen was located at a significantly shorter average distance of 2.05 +/- 0.03 A. High magnesium acetate (300 mM) completely inactivates primase in a reversible manner such that the region near the zinc ligands becomes accessible to proteolytic digestion [Urlacher, T. M., and Griep, M. A. (1995) Biochemistry 34, 16708-16714]. In this inactive complex, additional oxygen/nitrogen ligands from acetate as well as the histidine nitrogen are located at a distance of 2.20 +/- 0.03 A from the zinc site. To test whether the catalytic magnesium was binding within approximately 5 A of the zinc, we incubated primase with high (300 mM) manganese acetate. The functional properties of magnesium and manganese are similar, but the larger atomic number of manganese enhances the X-ray backscattering, making it possible to identify. Since no significant difference was observed from the manganese-incubated sample, the catalytic metal-binding site is likely located >5 A from the zinc. These studies clearly show that primase zinc ligation changes upon binding substrates.     

Copper(II) Complexes of Amino Acids and Peptides Containing Chelating bis(imidazolyl) Residues

Copper(II) complexes of amino acids and peptides containing the chelating bis(imidazolyl) residues have been reviewed. The results reveal that bis(imidazolyl) analogues of these biomolecules are very effective ligands for metal binding. The nitrogen donor atoms of the chelating agent are the major metal binding sites under acidic conditions. In the presence of terminal amino group the multidentate character of the ligands results in the formation of various polynuclear complexes including the ligand and the imidazole bridged dimeric species. The most intriguing feature of the coordination chemistry of these ligands is that the deprotonation of the coordinated imidazole-N(1)H groups results in the appearance of a new chelating site in the molecules. It leads to the formation of stable trinuclear complexes via negatively charged imidazolato bridges.     

Influence of solvent, anion and presence of nitrogen in the ring structure on the mechanism of complexation of alkali metal cations with crown ethers

The mechanism of complexation of alkali metal cations with macrocyclic ligands such as the simple crown ethers and the role of desolvation vs. ligand rearrangement are discussed. The unique role of water solvent in the rate-determining step of complexations in aqueous solutions is brought into focus. The competitive role of the anion, which becomes of paramount importance in solvents of low permittivity, is reiterated. Monoazo crown ethers are shown to possess isomeric equilibria in methanol solvent. The rate-determining process for the first step of complexation of these macrocycles with Na+ in methanol appears to be the rearrangement of the ligand through inversion to an exo position of the nitrogen lone electron pair. The rate-determining step of the overall complexation is the entrance of the Na+ into the ring with (possibly) concomitant rotation of the lone electron of the nitrogen to an endo configuration.     

Structure and antimicrobial activity of some new azopyrazolone chelates of Ni(II) and Cu(II) acetates, sulfates, and nitrates

Four coordinate Ni(II) and Cu(II) chelates formed by reaction of two azopyrazolone derivatives with metal sulfate, acetate, or nitrate are described. It is concluded that the ligands possess tautomeric equilibria and can coordinate to the metal ion as neutral or monobasic bidentates. The so-obtained complexes are characterized by elemental and thermal analyses, IR and electronic spectra, as well as conductivity measurements. A pseudo-tetrahedral polymeric structure is proposed for all the complexes in which the acetate, nitrate, or sulfate is attached to the metal ion in the bridging bidentate mode. It is observed that the chelates formed are more potent as antimicrobial agents than the free ligands.     

Identification of the six ligands to manganese(II) in transition-state-analogue complexes of creatine kinase: oxygen-17 superhyperfine coupling from selectively labeled ligands

The complete coordination scheme for Mn(II) in transition-state-analogue complexes with creatine kinase has been determined by electron paramagnetic resonance (EPR) spectroscopy. Perturbations in the EPR spectra for Mn(II) due to superhyperfine coupling to 17O of selectively labeled ligands have been used to identify oxygen ligands in the first coordination sphere of the metal ion. The results show that in the complex of enzyme-MnADP-formate-creatine, Mn(II) is bound to oxygen ligands from both the alpha- and beta-phosphate groups of ADP, to an oxygen from the carboxylate group of formate, and to three water molecules. In the complex with thiocyanate replacing formate as the stabilizing anion, previous infrared experiments [Reed, G. H., Barlow, C. H., & Burns, R. A., Jr. (1978) J. Biol. Chem. 253, 4153-4158] indicated that the nitrogen from thiocyanate was bound to the Mn(II). The magnitudes of the 17O superphyperfine coupling constants from the O- ligands of the ADP phosphate groups and from the formate carboxylate are approximately equal and are larger than that for the water ligands. The symmetry of the zero-field-splitting tensor for Mn(II) indicates that the oxygens from the alpha- and beta-phosphate groups of ADP and the ligand donor atom from the anion occupy mutually cis positions in the octahedral coordination geometry. Water proton relaxation time measurements show that the three water molecules which are bound to Mn(II) are not in free exchange with the bulk solvent. Hence, an enclosed structure at the active site is indicated. The results suggest that for creatine kinase the activating metal ion is bound to all three phosphate groups in the transition state of the reaction.     

Cd(II) and Cu(II) complexes of polydentate Schiff base ligands: synthesis, characterization, properties and biological activity

We report the synthesis of the Schiff base ligands, 4-[(4-bromo-phenylimino)-methyl]-benzene-1,2,3-triol (A₁), 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,2,3-triol (A₂), 3-(p-tolylimino-methyl)-benzene-1,2-diol (A₃), 3-[(4-bromo-phenylimino)-methyl]-benzene-1,2-diol (A₄), and 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,3-diol (A₅), and their Cd(II) and Cu(II) metal complexes, stability constants and potentiometric studies. The structure of the ligands and their complexes was investigated using elemental analysis, FT-IR, UV-Vis, ¹H and ¹³C NMR, mass spectra, magnetic susceptibility and conductance measurements. In the complexes, all the ligands behave as bidentate ligands, the oxygen in the ortho position and azomethine nitrogen atoms of the ligands coordinate to the metal ions. The keto-enol tautomeric forms of the Schiff base ligands A₁-A₅ have been investigated in polar and non-polar organic solvents. Antimicrobial activity of the ligands and metal complexes were tested using the disc diffusion method and the strains Bacillus megaterium and Candida tropicalis.Protonation constants of the triol and diol Schiff bases and stability constants of their Cu²⁺ and Cd²⁺ complexes were determined by potentiometric titration method in 50% DMSO-water media at 25.00 ± 0.02 °C under nitrogen atmosphere and ionic strength of 0.1 M sodium perchlorate. It has been observed that all the Schiff base ligands titrated here have two protonation constants. The variation of protonation constant of these compounds was interpreted on the basis of structural effects associated with the substituents. The divalent metal ions of Cu²⁺ and Cd²⁺ form stable 1:2 complexes with Schiff bases.The Schiff base complexes of cadmium inhibit the intense chemiluminescence reaction in dimethylsulfoxide (DMSO) solution between luminol and dioxygen in the presence of a strong base. This effect is significantly correlated with the stability constants K_CdL of the complexes and the protonation constants K_OH of the ligands; it also has a nonsignificant association with antibacterial activity.     

The metal-binding site of imidazole glycerol phosphate dehydratase; EPR and ENDOR studies of the oxo-vanadyl enzyme

 The apo protein of imidazole glycerol phosphate dehydratase (IGPD) from Saccharomyces cerevisiae combines stoichiometrically with certain specific divalent metal cations to assemble the catalytically active form comprising 24 protein subunits and tightly bound metal. VO²⁺ ions react similarly but, uniquely, result in a metallo-protein (VO-IGPD) with neither catalytic activity nor the ability to bind to the reaction intermediate analogue, 2-hydroxy-3-(1,2,4-triazol-1-yl) propylphosphonate. Since VO²⁺ apparently assembles the quaternary structure correctly, it is used in the present study as a spin probe to investigate the metal centre coordination environment by electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) spectroscopy. At neutral pH, the EPR spectrum of VO-IGPD reveals at least three distinct VO²⁺ sub-spectra with one predominant at low pH. The spin Hamiltonian parameters for some of the sub-spectra are consistent with ⁵¹V having nitrogen in the inner-sphere equatorial coordination environment from, most probably, multiple coordinating histidines. Further evidence for inner-sphere nitrogen ligands is obtained from ENDOR spectroscopy. The spectra of the low rf region show signals from interactions with ¹⁴N which are consistent with couplings to the imino nitrogen of coordinated histidine residues. In addition a number of proton ENDOR line pairs are resolved. Of the few that disappear upon exchange of the protein into D₂O, one most likely originates from the exchangeable proton of the N-H group of a coordinated histidine imidazole. ¹H-ENDOR line pairs from non-exchangeable protons with splittings of approximately 3 MHz can be attributed to imidazole carbon protons. Thus, most of the couplings observed by ENDOR are consistent with being from the imidazole heterocycle of one or more histidine ligands. Received: 27 June 1996 / Accepted: 14 March 1997     

Solution structure of Fe(II)–azide–bleomycin derived from NMR data: transition from Fe(II)–bleomycin to Fe(II)–azide–bleomycin as derived from NMR data and structural calculations

The coordination cage of the metal center in Fe(II)-bleomycin has been proposed to consist of the secondary amines in β-aminoalanine, the pyrimidinylpropionamide and imidazole rings, and the amide nitrogen in β-hydroxyhistidine as equatorial ligands, and the primary amine in β-aminoalanine and either the carbamoyl group in mannose or a solvent molecule occupying the axial sites. With the aim of supporting or not supporting coordination of a water molecule to the metal center in Fe(II)-bleomycin, the solution structure of Fe(II)-azide-bleomycin has been derived from NMR data. The structural changes that occur in Fe(II)-bleomycin upon azide binding have been monitored by comparing the experimental results with those obtained from the calculated structures for both bleomycin adducts. The results of this investigation strongly support a model of Fe(II)-bleomycin with six endogenous ligands as the most likely structure held in solution by this metallobleomycin in the absence of DNA.     

Model studies on the coordination of copper in biological systems. The deprotonated peptide nitrogen as a potential binding site for copper(II)

1. A large number of potentially bidentate and tridentate amides, X-Y-CONH-Z, were used as model ligands to investigate the complex formation of Cu(II) with the deprotonated peptide nitrogen in biological molecules. A combination of potentiometric titration, spectrophotometry and electron paramagnetic resonance was applied to analyse the structure of the Cu(II) chelates formed at neurtal and basic pH. 2. By systematic variation of the primary binding function X, the ring size of the chelate, and the spatial properties of the C-terminal and N-terminal substituents, three classes of amide ligands could be established with reference to their capacity for Cu(II)-induced deprotonation of NHCO and metal binding. 3. Under physiological conditions of pH, peptide (class A) chelates are only formed by those bidentate amide ligands with X being an imidazole (sp2) nitrogen or a terminal (sp3) amino nitrogen. Mercaptide sulfur must also be considered to belong in this group of strong copper(II)-binding sites, but in our low-molecular-weight model ligands the redox equilibrium 2 Cu(II) + 2 RSH in equilibrium or formed from 2 CU(II) + RSSR + 2 H+ interferes, yielding insoluble Cu(I)-S polymers above pH 4. In addition to the unidentate binding strength of X, entropy effects play an important role. Depending on whether X is an imidazole or amino nitrogen, only five-membered or six-membered monocyclic chelate structures respectively cause coordination of the deprotonated peptide function. 4. Biuret (class B) Cu(II) chelates are only formed under non-physiological conditions at pH > 11.5 producing the well known violet chromophores CuIIN4(-). In general these complexes, which also include the Cu(II) biguanides, show a clearly resolved electron paramagnetic resonance spectrum with nitrogen superhyperfine structure. 5. A third class of peptide model ligands (class C) consists of those amides where the CuII-X bond does not provide enough thermodynamic stability. The binding site of these class C amides includes functional groups such as carboxylate (COO-), methionine sulfur (RSR'), aliphatic or aromatic hydroxyl (OH) and amide nitrogen (NHCO) itself. When X is a pyridine (sp2) nitrogen or an amino (sp3) nitrogen, NHCO deprotonation is only promoted in five-membered but not six-membered ring chelates. On the other hand, a combination of COO- and NH2, as in asparagine, will allow deprotonation of NHCO in the presence of Cu(II). And third, despite a pronounced unidentate affinity of the imidazole nitrogen for Cu(II), N-acetylhistamine acts as a class C amine, in contrast to imidazolylacetamide, which forms a stable Cu(II) peptide chelate. This difference in Cu binding is explained on the basis of space-filling models. These clearly demonstrate that in the case of the 2:1 complex of Cu(II) with N-acetylhistamine, the planarity of the ionised peptide function can not be retained in a square planar arrangement of the two amide ligands around the copper center.