Chromium(III) complexes and their relationship to the glucose tolerance factor. Part II. Structure and biological activity of amino acid complexes

A number of octahedral chromium complexes with amino acids are ligands have been prepared and their structures assigned on the basis of their chromatographic and spectral properties. These include complexes with the general structure Cr(AA)₂(H₂O)₂ where the amino acids glycine, glutamic acid and glutamine act as bidentate ligands. The analogous compound with cysteine as ligand is stable at low pH, but at high pH a terdentate cysteine complex, Cr(cysteine)₂^?, is formed. These complexes, as well as a solution of monodentate glycine aquo complexes, and Cr-nicotinic acid-glycine and Cr-nicotinic acid-cysteine complexes of undetermined structure, have been assayed for glucose tolerance factor activity using a yeast assay. Only Cr(glutamine)₂- (H₂O)₂⁺, Cr-nicotinic acid-glycine and the mixture of complexes Cr(glycine)_n(H₂O)_6-n⁺³ showed significant activity. It is proposed that a trans arrangement of the non-coordinated nitrogen atoms in the ligands of these complexes can mimic the structural features of the glucose tolerance factor which are essential for biological activity.     

Structural components of alginic acid. I. The crystalline structure of poly-beta-D-mannuronic acid. Results of x-ray diffraction and polarized infrared studies

A Structure determination of the naturally occuring marine algal polysaccharide poly-β-D -mannuronic acid is described. The structure consists of 1e → 4e linked D -mannuronic acid chains with the monosaccharide units in the C1 chair conformation. The X-ray fiber diffraction photograph obtained from bundles of fibers prepared from Fucus vesiculosus has been indexed to an orthorhombic unit cell in which a =7.6 Å, b (fiber axis) = 10.4 Å, c = 8.6 Å, the unit cell containing two disaccharide chain segments with space group P2₁2₁2₁. A sheet-like structure involving one intra-chain, one intra-sheet, and one inter-sheet hydrogen bond per monosaccharide is proposed. Features of the chain-packing arrangement are compared with mannan.     

Toxicity of platinum(II) amino acid (N,O) complexes parallels their binding to DNA as measured in a new solid phase assay involving a fluorescent HMG1 protein construct readout

 The compound [Pt(lysine)Cl₂] (Kplatin) was previously identified in a study of platinum amino acid complexes as a potential antitumor drug candidate. The DNA binding properties, high mobility group (HMG)-domain protein affinity for the platinated DNA, and cytotoxicity against HeLa cells of Kplatin and three related (N,O) chelated platinum(II) amino acid complexes, [Pt(arginine)Cl₂] (Rplatin), K[Pt(N_e-acetyllysine)Cl₂] (NacKplatin), and K[Pt(norleucine)Cl₂] (Norplatin), are reported. The four complexes have identical PtCl₂(N,O) coordination environments. A new solid phase screening methodology was devised in which platinated DNA probes are covalently attached to a nylon support and tested for their ability to bind a fluorescently labeled HMG-domain protein. The fluorescent HMG-domain protein was generated by expressing a fusion of the green fluorescent protein (GFP) with recombinant rat HMG1. Binding revealed by the solid phase method correlated well with the results of gel mobility shift and HeLa cytotoxicity assays. These results suggest that the net charge on the complex, rather than the nature of the side chain, is the most important factor underlying the DNA binding properties and toxicity of amino acid (N,O) chelated platinum complexes. This property explains why Kplatin was previously selected from the pool of platinum amino acid complexes based on the ability of its DNA adducts to bind HMG1. Received: 3 February 1999 / Accepted: 7 April 1999     

Synthesis, characterization and 1D helical chain crystal structure of [Cu(DBA)2(1,10-phen)]n and [Cd(DBA)2(1,10-phen)2] (DBA = benzilic acid)

Two novel complexes [Cu(DBA)₂(1,10-phen)]_n (1) and [Cd(DBA)₂(1,10-phen)₂] (2) [HDBA = benzilic acid: (C₆H₅)₂C(OH)COOH] have been synthesized and characterized by element analysis and fluorescence spectroscopy. The crystal structures of compounds 1, 2 and HDBA (3) were also determined. Complex 1 is a one-dimensional (1D) helical infinite chain, in which [(1,10)-phen]Cu^(II) units were bridged by benzilic acid. Complex 2 is a mononuclear structure, and is self-assembled through π-π stacking interactions to form a 1D helical chain. Compound 3 is self-assembled to form a 1D helical chain through hydrogen bonds interactions. Thermal analyses indicate that complexes 1 and 2 are stable under 200 and 254 °C in solid state, respectively.     

Preparation and characterization of two supramolecular complexes with 5-amino-2,4,6-triiodoisophthalic acid under N-donor auxiliary ligand intervention

Assemblies of 5-amino-2,4,6-triiodoisophthalic acid (H₂ATIBDC) with Cd(II) and Zn(II) in the presence of N-donor auxiliary ligand, 1,4-bis(1,2,4-triazol-1-yl)butane (btb), at ambient conditions yield two new supramolecular complexes, [Cd(ATIBDC)(btb)(H₂O)₂]·3H₂O (1), and [Zn(ATIBDC)(btb)]·2H₂O (2). Generally, these two complexes display 1D ATIBDC²⁻-bridged coordination arrays. Distinct extended 3D network architectures are further constructed with the help of weak secondary interactions especially aromatic stacking, halogen bonding, and hydrogen bonding as supramolecular driving forces. It is worthy to mention that halogen bonds (C-I?π and C-I?N/O) play important roles in the supramolecular assembly. The pentameric cluster (H₂O)₅ in 1 assembles into highly ordered helical infinite chains. Complex 2 exhibits the fascinating single-walled tube-like chain structure. It loses crystallinity rapidly in the air and leads to the formation of [Zn(ATIBDC)(btb)]·H₂O (2A). Thermal stabilities and solid state fluorescent properties of complexes 1 and 2A have been studied.     

Antitumor activity of titanocene amino acid complexes

Seven ionic titanocene -amino acid (aa) complexes [(C₅H₅)₂Ti(aa)₂]²⁺[X]₂ ^– with aa = glycine,l-alanine, 2-methylalanine,d-l-phenylalanine,d,l-4-fluorophenylalanine and X = Cl or AsF₆, were investigated for antitumor activity against fluid Ehrlich ascites tumor growing in CF1 mice. These complexes are the first stable model compounds of titanocene units with protein components, synthesized from a water-like, methanolic medium. All titanocene amino acid complexes induced antitumor activity which was manifested by maximum cure rates ranging from 30 to 70% and increases in life span from 78 to 276% in comparison with untreated control animals. The complexes containing chloride as anion X were more effective than the hexafluoroarsenate derivatives, which surprisingly showed a low substance toxicity. In all cases, the antitumor activity of the ionic titanocene amino acid complexes tested was less pronounced than that of the neutral parent compound [(C₅H₅)₂TiCl₂].     

Neutral mononuclear dioxomolybdenum(VI) and dioxouranium(VI) complexes of oxolinic acid: Characterization and biological evaluation

The interaction of the first-generation quinolone antibacterial drug oxolinic acid (Hoxo) with the dioxomolybdenum(VI) and dioxouranim(VI) ions leads to the formation of the neutral mononuclear complexes MoO₂(oxo)₂ and UO₂(oxo)₂, respectively. The structure of the complexes has been characterized physicochemically and spectroscopically. The lowest energy model structure of the complexes has been determined with molecular modeling calculations. The antimicrobial activity of the complexes has been evaluated against three different microorganisms. The interaction of the complexes with calf-thymus DNA has been investigated with electronic and circular dichroism spectroscopies.     

Iron(III) and aluminum(III) complexes with hydroxypyrone ligands aimed to design kojic acid derivatives with new perspectives

With the aim to design new chelators for the clinical treatment of different diseases involving the trivalent metal ions Fe(III) and Al(III), we present the equilibria of kojic acid and its derivative 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one with these two metal ions. Potentiometric and spectrophotometric techniques for iron, and potentiometry and ¹H NMR for aluminum were used, supported by X-ray, electrospray ionization-mass spectrometry (ESI-MS), calorimetry and quantum chemical calculations. In this work, evidence is given on the formation of MeL, MeL₂, and MeL₃ complexes of both metal ions with kojic acid, confirmed by the X-ray structure of the FeL₃ complex, and of variously protonated Me₂L₂ and MeL₂ complexes of 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one. The extremely good pFe value for this second ligand gives confidence to, and opens perspectives for, the search of new kojic acid derivatives.     

Surfactant–copper(II) Schiff base complexes: synthesis,structural investigation,DNA interaction,docking studies,and cytotoxic activity

A series of surfactant–copper(II) Schiff base complexes (1–6) of the general formula, [Cu(sal-R₂)₂] and [Cu(5-OMe-sal-R₂)₂], {where, sal?=?salicylaldehyde, 5-OMe-sal?=?5-methoxy- salicylaldehyde, and R₂?=?dodecylamine (DA), tetradecylamine (TA), or cetylamine (CA)} have been synthesized and characterized by spectroscopic, ESI-MS, and elemental analysis methods. For a special reason, the structure of one of the complexes (2) was resolved by single crystal X-ray diffraction analysis and it indicates the presence of a distorted square-planar geometry in the complex. Analysis of the binding of these complexes with DNA has been carried out adapting UV-visible-, fluorescence-, as well as circular dichroism spectroscopic methods and viscosity experiments. The results indicate that the complexes bind via minor groove mode involving the hydrophobic surfactant chain. Increase in the length of the aliphatic chain of the ligands facilitates the binding. Further, molecular docking calculations have been performed to understand the nature as well as order of binding of these complexes with DNA. This docking analysis also suggested that the complexes interact with DNA through the alkyl chain present in the Schiff base ligands via the minor groove. In addition, the cytotoxic property of the surfactant–copper(II) Schiff base complexes have been studied against a breast cancer cell line. All six complexes reduced the visibility of the cells but complexes 2, 3, 5, and 6 brought about this effect at fairly low concentrations. Analyzed further, but a small percentage of cells succumbed to necrosis. Of these complexes (6) proved to be the most efficient aptotoxic agent.     

Interaction of poly-5-bromouridylic acid. I. Formation of helical complexes with various adenine and 2-aminoadenine derivatives

Complexes of poly(BU) with various adenine derivatives were investigated by circular dichroism (CD) and absorption spectroscopy. A 1:2 stoichiometry was indicated on CD mixing curves for typical complexes of 9-substituted adenine and 2-aminoadenine derivatives with poly(BU). The CD spectrum of adenosine·2poly(BU) is characterized by well-resolved bands in the range of 210–350 nm. Other adenine derivative–poly(BU) complexes also afford similar CD spectra, while 2-aminoadenine derivative–poly(BU) complexes give quite different spectra. Attempts to assign representative CD spectra were made using the transition of helical poly(BU) and the respective purine polynucleotides. The similarity of the CD spectra suggests that poly(A)·2poly(BU) and adenine derivative–poly(BU) complexes are nearly identical in structure except for the ribose–phosphate linkage. The fact that the uv isosbestic point of adenosine·2poly(BU) falls in close proximity to that of the corresponding polymer complex also supports this conclusion. In the formation of stable helices, the ribose moiety is dispensable in the “strand” of purine. The T_m of 9-methyladenine·2poly(BU) is somewhat higher than that of adenosine·2poly(BU) under equivalent conditions. The T_m difference with the monomer–poly(U) system was found to be about 20°C in 0.4M NaCl–0.02M Na–cacodylate–5 × 10^?4M EDTA (pH 7.0). Further, it was noted that the monomer–poly(BU) complexes are formed even when the T_m is lower than that of self-folded poly(BU).     

One pot synthesis of Cu(II) 2,2'-bipyridyl complexes of 5-hydroxy-hydurilic acid and alloxanic acid: synthesis, crystal structure, chemical nuclease activity and cytotoxicity

A barbiturate derivative [1,5-dihydro-5-[5-pyrimidine-2,4(1H,3H)-dionyl]-2H-chromeno[2,3-d] pyrimidine-2,4(3H)-dione] (LH₄) was allowed to react with 2,2′-bipyridyl-dinitrato-Copper(II)-dihydrate which provides two complexes, characterized as [Cu(bpy)(L1)]·3H₂O () and [Cu(bpy)(L2)]·H₂O (), where bpy = 2,2′-bipyridine, L1 = 5-hydroxy-hydurilic acid and L2 = alloxanic acid. In a separate reaction of LH₄ with Cu(NO₃)₂·H₂O another type of complex [Cu(LH₃)₂·(H₂O)₂]·4H₂O () is formed. The complexes were characterized by single crystal X-ray crystallography, physicochemical and electrochemical studies. The interaction of complexes 1 and 3 with DNA was monitored using absorption and emission titrations as well as circular dichroism spectroscopy. The complexes were found to cleave supercoiled plasmid DNA to nicked circular and linear DNA. Complexes 1 and 3 were also tested against T-cell lymphoma (Dalton lymphoma DL) and showed significant cytotoxic activity with IC₅₀ values of ~ 9.0 nM and 0.6 nM.     

Syntheses and characterization of cobalt(II) complexes of dimeric ‘picket fence’ porphyrins

A series of dimeric picket fence porphyrinatocobalt(II) complexeses in which the length of the bridging chain controls the dioxygen affinity was newly derived from the coupling of two meso-mono- (β-o-aminophenyl)-tris-(α,α,α-o-pivaloylamidophenyl)- porphyrins with (CH₂)_n(COCl)₂ (n = 1, 3, 5 or 7). Some of the dimeric complexes form a unique ‘sandwich structure’ upon binding with certain bidentate ligands, and their dioxygen affinities are greatly increased compared with those for corresponding monomeric complexes. The relationship observed between the length of the bridging chain and the dioxygen affinity of the dimer complex having a sandwich structure is interpreted in terms of the displacement mechanism of the metal atom from a porphyrin plane.     

An unexpected by-product obtained during the preparation of technetium(III) boronic acid adducts of dioximes. The single crystal structure of TcCl(DMG)2(BDI)BEt (DMG=dimethylglyoxime, BDI=butane-2, 3-dione imine-oxime)

An unusual Tc(III) boron-capped imine-oxime complex has been isolated from the reaction of ⁹⁹TcCl₃(CH₃CN)(PPh₃)₂, dimethyl glyoxime (DMG) and ethyl boronic acid (EtB(OH)₂). A single crystal X-ray structure analysis of this molecule ⁹⁹TcCl(DMG)₂(BDI)BEt (BDI=butane-2, 3-dione imine-oxime) shows it to be seven coordinate: TcClC₁₄H₂₅N₆O₅B, a=9.073(2), b=23.686(5), c=19.539(6) Å; β=93.77(2)°, P2₁/n, Z=8. Its structure is very similar to that of previously reported Tc(III) complexes ⁹⁹TcCl(dioxime)₃BR, except that one dioxime ligand on the molecule has been reduced to an imineoxime.     

Syntheses and crystal structures of the metal complexes based on pyrazolecarboxylic acid ligands

This paper aims at introducing five new metal complexes, Co(HL₁)₂(H₂O)₂ (1), {[Cu(HL₁)₂] · (H₂O)}_n (2), {[Zn(HL₂)(H₂O)₃] · 2H₂O}_n (3), {[Co(HL₂)(H₂O)₃] · 2H₂O}_n (4) and [K(H₂L₂)]_n (5), (in which H₂L₁ is 3-methyl-5-pyrazolecarboxylic acid and H₃L₂ is 3,5-pyrazoledicarboxylic acid, respectively), which have been synthesized under hydrothermal conditions or by using diffusion methods. Their molecular structures have been characterized by elemental analyses, IR spectroscopy and single-crystal X-ray diffraction analyses. The X-ray analyses reveal that complex 1 has a mononuclear structure, which is further assembled to a three-dimensional (3-D) framework through intermolecular hydrogen bonds; complex 2 is a 1-D coordinated polymer, which is further assembled to a 2-D layer through intermolecular hydrogen bonds and π–π interactions; both complexes 3 and 4 possess similar 1-D chain structures, and the adjacent chains are further linked by hydrogen bonds to form 2-D supramolecular networks; complex 5 exhibits a 3-D structure, in which, the metal–metal weak interaction, K–K, plays an important role.     

Topography of cyclodextrin inclusion complexes : Part I. Classification of crystallographic data of α-cyclodextrin inclusion complexes

The crystallographic and stoichiometric data obtained for 17 different inclusion complexes of α-cyclodextrin are reported. The cell dimensions and space-group symmetries reflect the packing arrangement of the torus-shaped host molecules and are largely determined by the size and ionic character of the guest molecules.In the series acetic acid, propionic acid, butyric acid, valeric acid, the first three complexes with α-cyclodextrin crystallize in a cage-type structure with space group P2₁2₁2₁, which is characteristic or small, non-ionic guest molecules. The valeric acid molecule seems to be too long to be accommodated in a cage structure; thus, the α-cyclodextrin molecules are arranged such that a structure consisting of parallel channels is formed. This packing is typical for the inclusion of long, thin, or ionic guest molecules. A third class of complexes with structures differing from the two described was also observed.A correlation exists between the type of inclusion complex and the volume required for a complex molecule: 1200–≈ 1400 ų for molecular guests, and 1400–1500 ų for ionic guests.     

Potentiometric and spectroscopic studies on Cu(II) complexation to aminophosphonic acid, 1-(3-pyridyl)-1-(n-butylamino)-methanephosphonic acid

The results are reported of a potentiometric and spectroscopic study of the copper(II) complexes of aminophosphonic acid containing a pyridyl side chain. The aminophosphonic acid coordinates similarly to carboxyl amino acids, forming chelate MA and MA₂ species. Stable MAH species with only a phosphonic group coordinated to the metal ion exist at lower pH. The pyridyl side chain was found to be noneffective in the interaction with Cu(II) ion.     

NAR Breakthrough Article: Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation

ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N⁶-methyladenine in RNA. ALKBH5 is upregulated under hypoxia and plays a role in spermatogenesis. We describe a crystal structure of human ALKBH5 (residues 66–292) to 2.0 Å resolution. ALKBH5_66–292 has a double-stranded β-helix core fold as observed in other 2OG and iron-dependent oxygenase family members. The active site metal is octahedrally coordinated by an HXD…H motif (comprising residues His204, Asp206 and His266) and three water molecules. ALKBH5 shares a nucleotide recognition lid and conserved active site residues with other NAOXs. A large loop (βIV–V) in ALKBH5 occupies a similar region as the L1 loop of the fat mass and obesity-associated protein that is proposed to confer single-stranded RNA selectivity. Unexpectedly, a small molecule inhibitor, IOX3, was observed covalently attached to the side chain of Cys200 located outside of the active site. Modelling substrate into the active site based on other NAOX–nucleic acid complexes reveals conserved residues important for recognition and demethylation mechanisms. The structural insights will aid in the development of inhibitors selective for NAOXs, for use as functional probes and for therapeutic benefit.     

Study on the reaction of 2,3-dihydroxybenzoic acid with molybdenum in aqueous solution. I. Synthesis and characterization of the oligomeric complexes formed

Dimeric or oligomeric oxo-complexes of Mo(VI) with 2,3-dihydroxybenzoic acid were prepared in aqueous solutions in the presence or not of K₂S₂O₅ (acting as a reducing agent) in various conditions. The complexes were found to contain the cis-(Mo₂O₅)²⁺ core and the ligands in the catecholate, semiquinonate or mixed valence oxidation form, depending on the reaction conditions and especially on the presence or not of the reductant. The isolated complexes in the presence or absence of reductant and the oxidation products in solution in the presence of air were studied via elemental, thermogravimetric and electrochemical analysis, Infrared, Raman, NMR and ESR spectroscopies and Electrospray Mass Spectra. The general molecular formula for the complexes is {[(PPh₄)₂(Mo₂O₅L₂X₂] · xH₂O)}_n, where the coordinated ligand’s L oxidation form varies and X involves coordinated water or hydroxyl group depending on the ligand oxidation state.     

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.     

An investigation by ion-exchange chromatography of a chromium,amino acid and nicotinic acid mixture

The mixture of chromium, nicotinic acid and the amino acids glycine, glutamic acid and cysteine which stimulates the rate of CO₂ production in a yeast bioassay system was subjected to the separation scheme based on ion-exchange chromatography which has been used to separate the chromium- containing fractions in brewer's yeast, [S.J. Haylock, P.D. Buckley and L.F. Blackwell, J. Inorg. Biochem., 18, 195 (1983)]. Four chromium-containing fractions (C2 to C5) were obtained by salt gradients and two further fractions (G1 and G2) were obtained using a pH gradient. All were amino acid-containing complexes of chromium and all except C5 also contained nicotinic acid. However, none of the isolated chromium fractions showed any activity in a yeast bioassay. On the basis of previous work, the activity of the original mixture was attributed to the presence of an oxygen-coordinated trans chromium(III)-dinicotinate complex. Biologically- inactive chromium complexes such as Cr(glu)₂(H₂O)⁺₂ and Cr(gly)₂(H₂O)⁺₂ after elution by ammonium hydroxide from Dowex 50W-X12 cation- exchange columns, stimulated the rate of CO₂ production in the yeast bioassay. Elution with other bases, such as lithium hydroxide, potassium hydroxide and sodium hydroxide led to inactive fractions in all cases. A warning is therefore given that the use of ammonium hydroxide-elution of ion-exchange columns to isolate glucose tolerance factor fractions from biological samples (such as brewer's yeast) can lead to active fractions which do not relate to the native material.