Interactions of Al(acac)3 with cell membranes and model phospholipid bilayers.

Aluminum is a neurotoxic agent; however, little information has been obtained regarding its molecular cytotoxicity and the effects on the stability of biological membranes. This is mainly due to the ill-defined chemical speciation of the metal compounds. For this reason, the present study used aluminum acetylacetonate, (Al(acac)3), a neutral, chemically well-defined, hydrolytically stable and lipophilic compound. To understand the molecular mechanism of its interaction with cell membranes, Al(acac)3 was incubated with human erythrocytes, isolated toad skin and molecular models of biomembranes. The latter consisted of multilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoyphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively. The results showed that Al(acac)3 interacted with the erythrocyte membrane modifying its normal discoid morphology to both echinocytic and stomatocytic shapes. This finding indicates that the Al complex was inserted in both the outer and inner layers of the red cell membrane, a conclusion supported by X-ray diffraction analyses of DMPC and DMPE bilayers. Electrophysiological measurements performed on toad skin revealed a significant decrease in the potential difference and short-circuit current responses after application of Al(acac)3, effects interpreted to reflect inhibition of the active transport of ions. Al(acac)3 was active on both surfaces of the skin suggesting that the membrane was permeated by the metal complex. It is concluded that Al(acac)3 both alters the molecular structure of the lipid bilayer, thereby modifying the biophysical properties of the cell membrane, and changes its physiological properties.     

Synthesis, characterization and antiamoebic activity of benzimidazole derivatives and their vanadium and molybdenum complexes

Reaction of [MoO(2)(acac)(2)] (where, acac=acetyl acetone) and KVO(3) with 2-(salicylidieneimine) benzimidazole lead to form new complexes [MoO(2)(sal-BMZ)(2)] and K [VO(2)(sal-BMZ)(2)] [where, sal-BMZ=2-(salicylidieneimine) benzimidazole], which showed the monobasic bidentate nature of the ligand in which the phenolic oxygen and the imine nitrogen of the ligand are coordinated to the metal ion. These complexes were characterized along with nine other complexes of oxoperoxovanadium (V), molybdenum (Vl) and tungsten (Vl) with benzimidazole derivatives and screened in vitro by micro dilution technique for their amoebicidal activity with a view to search for a more effective agent against Entamoeba histolytica suggests that compound 2 and 3 might be endowed with important antiamoebic properties since they showed IC(50 )values in a microM range.     

Chlorido-, aqua-, 9-ethylguanine- and 9-ethyladenine-adducts of cytotoxic ruthenium arene complexes containing O,O-chelating ligands

The synthesis and X-ray structures of a half-sandwich Ru(II)p-cymene beta-diketonato complex as chlorido-, aqua-, 9-ethylguanine- and 9-ethyladenine-adducts are reported. Structural features which contribute to stabilisation of adducts through non-covalent, weak interactions are discussed. The X-ray crystal structure of the cytotoxic complex [(eta(6)-p-cym)Ru(Ph(2)acac)Cl] (1), where Ph(2)acac=1,3-diphenyl-1,3-propanedionate and p-cym=para-cymene, shows that the phenyl rings of the acac-type ligand form a hydrophobic face, conferring lipophilic character on the complex. The structure of the aqua adduct [(eta(6)-p-cym)Ru(Ph(2)acac)H(2)O]CF(3)SO(3).H(2)O.Et(2)O (4.H(2)O.Et(2)O), a possible activated species, possesses a comparatively short Ru-OH(2) bond. In the structure of [(eta(6)-p-cym)Ru(Ph(2)acac)9EtG-N7]CF(3)SO(3).2tol (5.2tol), where tol=toluene and 9EtG=9-ethylguanine, a comparatively long Ru-N7 bond is observed in addition to weak G CH8cdots, three dots, centeredO (Ph(2)acac) H-bonds. The crystal structure of [(eta(6)-p-cym)Ru(acac)9EtA-N7]PF(6) (6), where acac=acetylacetonate and 9EtA=9-ethyladenine, a rare example of a ruthenium complex containing monodentate adenine, shows a strong H-bonding interaction between N6Hcdots, three dots, centeredO(acac), which may contribute to the selectivity of {(eta(6)-p-cym)Ru(acac)}(+) towards adenine bases.     

Optical resolution and racemisation of [Fe(acac)3]

Optical resolution of [M(acac)₃] complexes, where acac⁻ is the acetylacetonato ligand, was achieved decades ago for metal ions such as Co³⁺ and Cr³⁺, i.e. for metal ions forming configurationally inert complexes. Complete optical resolution of [Fe(acac)₃] have so-far been unsuccessful due to the high rate of racemisation. By means of spontaneous resolution of its carbon tetrachloride solvate, we have been able to prepare optically pure samples of [Fe(acac)₃]. These samples displayed circular dichroism in the solid state, as well as in diethyl ether solution, and the CD-spectra could be correlated to the correct absolute configuration. Using CD-spectroscopy, the optical half-life was estimated to be 3.3 min in diethyl ether solution at ambient temperature. In the same solvent, no sign of racemisation was observed after 23 h at −80 °C. Racemic [Fe(acac)₃] is a useful catalyst in organic synthesis.     

X-ray structure, solution properties, and biological activity profile of vanadocene(IV) acetylacetonate complex,

The structure of [V(eta5-C5H5)2(CH3C(O)CHC(O)CH3)](O3SCF3) (1) (=[VCp2(acac)](O3SCF3)), a dual-function anti-cancer agent with anti-angiogenic and anti-mitotic properties, was determined by single-crystal X-ray diffraction. The geometry is well described as a pseudo-tetrahedral like structure with the centroids of the cyclopentadienyl rings and the two oxygen atoms of the acetylacetonate ring in the ancillary positions of the central vanadium (IV) atom. The bisector of the V(acac) fragment deviates from the C2 axis of the ligand framework by only 4 degrees, compared to a deviation of 7 degrees for the V(acac) fragment in the tetramethylethano-bridged vanadocene acetyl acetonate complex. Crystal data for 1: space group, P2(1)/c; a=7.5544(9) A, b=14.936(2) A, c=16.193(2) A, beta=102.901(2) degrees, V= 1781.0(4) A3; Z=4; R=0.0506 for 2310 reflections with I> 2sigma(I). This report also details the electron paramagnetic resonance, UV/Vis spectroscopy, electrochemical properties and the biological activity profile of this potent anti-cancer agent.     

Mixed ligand complexes of lanthanides with macrocyclic and open-chained polyaminopolycarboxylic acids and acetylacetone

Studies of mixed ligand complex formation stabilities and dissociation kinetics have been performed on lanthanide ions with macrocyclic and open- chained polyaminopolycarboxylic acids (i.e. DAPDA, DACDA, EDDA, and EDTA) and acetylacetone (acac). From UV spectroscopic evidence, it was found that Ln(DACDA)⁺ and Ln(EDTA)⁻ complexes do not form mixed ligand complexes with acac under the set conditions, i.e. pH = 7.2 and complex concentration of 1 x 10⁻⁴ M. On the other hand, formation of Ln(DAPDA)(acac) and Ln(EDDA)(acac)₂⁻ complexes were readily detectable. The mixed complex forma- tion constants,β₁, for the equilibrium Ln(L)⁺ + acac⁻ ⇌ Ln(L)(acac), and β₂, for the equilibrium Ln(L)⁺ + 2 acac⁻ ⇌ Ln(L)(acac)₂⁻ were determined by potentiometric titration technique where possible. It was found that β₁ values were in general greater for Ln(EDDA)⁺ complexes than for Ln(DAPDA)⁺ complexes indicating the resulting reduced charge density at the lanthanide ion of Ln(DAPDA)⁺ and that less space is available for the acetylacetone moiety to coordinate to the Ln(DAPDA)⁺ complexes due to the large size and the greater number of coordination atoms of DAPDA. The hydrolysis constants of Ln(EDDA)(H₂O)_n⁺ species were also determined and were found to be increasing with increasing atomic number of Ln. Attempts to measure the acid assisted mixed ligand complex dissociation rates by a stopped-flow spectrophotometer were not fruitful due to the much faster rates.     

Structure and coordination properties of a tetrathiafulvalene derivative with an acetylacetone group

The synthesis and crystal structure of a new tetrathiafulvalene (TTF) derivative with an acetylacetone substituent are reported (3-(dimethylthio-TTF-thio)-2,4-pentane-dione, DMT-TTF-acac (1)). Compound 1 consists of a TTF plane and an acac plane, which are bridged by a sulfur atom. The bond distances and angles of 1 clearly indicate that the acetylacetone group adopts a keto-enol structure with an O-H?O intramolecular hydrogen bond. As usually observed for TTF derivatives, compound 1 exhibits two-step reversible redox waves on CV measurement, which are sensible to the metal ions being added. The stronger the metal coordination is, the larger the potential shift would be. Two complexes of 1, [M(DMT-TTF-acac)₂] M = Mn(II) and Cu(II), have been prepared and they are very stable even in the state in which the ligands are oxidized. The iodine-doped compound of Mn(II) is a new organic-inorganic system consisting of paramagnetic metal ions and organic radicals.     

A new tricarbonyl fac-[M(acac)(isc)(CO)3] complex (M = Re, Tc) with acetylacetonate (acac) and isocyanide (isc) in a 2+1 combination

The synthesis and characterization of the neutral 2+1 mixed ligand complex fac-Re(CO)₃(acac)(isc) (4) with acetylacetonate (acac) as the bidentate ligand and an isocyanide (the isocyanocyclohexane, isc) as the monodentate ligand is described. The synthesis of 4 proceeds through the intermediate formation of the fac-Re(acac)(H₂O)(CO)₃ precursor complex 2. Complex 4 was characterized by elemental analysis, spectroscopic methods, and X-ray crystallography showing a distorted octahedral arrangement of the ligands around Re. At technetium-99m level, the corresponding fac-^99mTc(acac)(isc)(CO)₃ complex 5 was obtained in high yield by reacting the fac-^99mTc(acac)(H₂O)(CO)₃ precursor complex 3 with isocyanocyclohexane and its structure was established by chromatographic comparison with the prototypic rhenium complex using high performance liquid chromatography.     

Synthetic analogue approach to metallobleomycins: syntheses, structure and properties of mononuclear and tetranuclear gallium(III) complexes of a ligand that resembles the metal-binding site of bleomycin

As part of our interest into the bioinorganic chemistry of gallium, gallium(III) complexes of the peptide ligand N-(2-(4-imidazolyl)ethyl)pyridine-2-carboxamide (pypepH2) resembling a fragment of the metal-binding domain of bleomycins (BLMs), have been isolated. Reaction of pypepH2 with (Et4N)[GaCl4] and Ga(acac)3 [acac- is the acetylacetonate(-1) ion] affords the mononuclear complex [Ga(pypepH)2]Cl.2H2O (1) and the tetranuclear complex [Ga4(acac)4(pypep)4].4.4H2O (2), respectively. Both complexes were characterized by single-crystal X-ray crystallography, IR spectroscopy and thermal decomposition data. The pypepH- ion in 1 behaves as a N(pyridyl), N(deprotonated amide), N(pyridine-type imidazole) chelating ligand. The doubly deprotonated pypep2- ion in 2 behaves as a N(pyridyl), N(deprotonated amide), N(imidazolate), N'(imidazolate) mu2 ligand and binds to one Ga(III) atom at its pyridyl, amide and one of the imidazolate nitrogens, and to a second metal ion at the other imidazolate nitrogen; a chelating acac- ligand completes six coordination at each Ga(III) centre. The IR data are discussed in terms of the nature of bonding and known structures. The 1H NMR spectrum of 1 suggests that the cation of the complex maintains its integrity in dimethylsulfoxide (DMSO) solution. Complexes 1 and 2 are the first synthetic analogues of metallobleomycins with gallium(III).     

XANES investigation of the Co oxidation state in solution and in cancer cells treated with Co(III) complexes

XANES spectroscopy has been used to investigate whether it is possible to determine the oxidation state and coordination environment of Co complexes following treatment of cancer cells with Co(III) or Co(II) complexes. Our results show that the variation of the XANES with coordination geometry make it impossible to do this in a completely reliable way which is in contrast to the situation for platinum and chromium. It was established that the XANES spectrum obtained from cells treated with [Co(diNOsar)]Br(3) remained unchanged with respect to its XANES spectrum obtained in solution, demonstrating that the [Co(diNOsar)]Br(3) complex remained intact after 24h in cellular media (diNOsar=1,8-dinitro-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane). In contrast, the XANES spectra obtained from cells treated with Na[Co(acac)(3)] and [Co(acac)(3)] differed from the XANES spectra of the respective complexes obtained in solution, indicating a change in co-ordination environment for both complexes upon uptake in cells. The similarity of these spectra suggests that appearance of this XANES can be used as an indication of loss of the carrier ligands, a useful indicator in the study of hypoxia selective complexes. The results obtained for Na[Co(acac)(3)] and [Co(acac)(3)] are consistent with the intracellular coordination of cobalt(III) to sulfur ligands upon cellular uptake.     

Synthesis, characterization, fluorescence and computational studies of new Cu, Ni and Hg complexes with emissive thienylbenzoxazolyl-alanine ligands

The interaction of four fluorescent compounds containing thiophene and benzoxazole moieties combined with an alanine residue with alkaline, alkaline-earth, transition and post-transition metal ions was explored. The highly fluorescent heterocyclic alanine derivatives are strongly quenched in the solid state after complexation with the paramagnetic metal ions Cu²⁺ and Ni²⁺, and with the diamagnetic Hg²⁺. Absorption and steady-state fluorescence titrations reveal a selective interaction with Cu²⁺, Ni²⁺ and Hg²⁺. In all cases the formation of mononuclear or dinuclear metal complexes in solid state and in solution are postulated. DFT calculations on the mercury(II) complexes confirm the formation of dinuclear species. Our results suggest that one metal ion is coordinated by the chelate group formed by the amine and the protonated carboxylic groups present in the amino acid residue while a second metal ion is directly linked to the chromophore. As parent compound, L4 shows no interaction with Cu²⁺ and Ni²⁺ salts. However, the interaction with Hg²⁺ induces a strong quenching and a red shift of the fluorescence emission.     

Stability constants for,and structural investigation of,divalent metal ion complexes with polyene antibiotics

The stability constants for the formation of complexes between Ca(II), Mg(II), Cu(II), Zn(II) and Ni(II) with nystatin and amphotericin-B (polyene antibiotics) have been determined by both a potentiometric and a solubility method. The structures of the complexes have been investigated by NMR, ESR and CD spectroscopy. The transition metal stability constants are consistent with the Irving- Williams series. The structural results are discussed and related to the importance of such complexes in mode of action theories.     

Structural origins of the insulin-mimetic activity of bis(acetylacetonato)oxovanadium(IV)

We have investigated the interaction of bis(acetylacetonato)oxovanadium(IV) (VO(acac)(2)) with bovine serum albumin (BSA) by EPR and angle-selected electron nuclear double resonance, correlating results with assays of glucose uptake by 3T3-L1 adipocytes. EPR spectra of VO(acac)(2) showed no broadening in the presence of BSA; however, electron nuclear double resonance titrations of VO(acac)(2) in the presence of BSA were indicative of adduct formation of VO(acac)(2) with albumin of 1:1 stoichiometry. The influence of VO(acac)(2) on uptake of 2-deoxy-d-[1-(14)C]glucose by serum-starved 3T3-L1 adipocytes was measured in the presence and absence of BSA. Glucose uptake was stimulated 9-fold in the presence of 0.5 mm VO(acac)(2), 17-fold in the presence of 0.5 mm VO(acac)(2) plus 1 mm BSA, and 22-fold in the presence of 100 nm insulin. BSA had no influence on glucose uptake, on the action of insulin, or on glucose uptake in the presence of VOSO(4). The maximum insulin-mimetic effect of VO(acac)(2) was observed at VO(acac)(2):BSA ratios less than or equal to 1.0. Similar results were obtained also with bis(maltolato)oxovanadium(IV). These results suggest that the enhanced insulin-mimetic action of organic chelates of VO(2+) may be dependent on adduct formation with BSA and possibly other serum transport proteins.     

Free radical mediated interaction of ascorbic acid and ascorbate/Cu(II) with viral and plasmid DNAs

Previous studies indicate that ascorbic acid, when combined with copper or iron cleaves several viral DNA. ln this study, we generated the ascorbate radical anion electrochemically in a simple chemical environment without the participation of a metal ion. This solution possesses viral DNA scission activity. Ohe absence of catalytic metal ions [Fe (III) and Cu(II)] in the incubation medium was evidenced by metal chelating agents such as desferrioxamine and EDTA. Ohe radical quenching at high EDTA concentration was attributed to ionic strength of EDTA rather than metal chelation. Ohe effects of antioxidants, radical scavangers, catalase, superoxide dismutase and some proteins on DNA cleavage have been tested. Cleavage may not arise directly from ascorbate free radical but the reaction of the radical form of ascorbate with oxygen may produce the actual reactive species. Aerobic oxidation of ascorbate itself strictly requires transition metal catalysts, however electrochemically produced ascorbyl radical avoided the kinetic barrier that prevented direct oxidation of ascorbic acid with oxygen and eliminated the need for the transition metal ion catalysts.     

Transition‐Metal (Fe,Co, Ni) Based Metal‐Organic Frameworks for Electrochemical Energy Storage

Transition‐metal (Fe, Co, Ni) based metal‐organic framework materials with controllable structures, large surface areas and adjustable pore sizes have attracted wide research interest for use in next‐generation electrochemical energy‐storage devices. This review introduces the synthesis of transition‐metal (Fe, Co, Ni) based metal‐organic frameworks and their derivatives with the focus on their application in supercapacitors and batteries.     

Reactions of oxobis(acetylacetonato)- vanadium(IV) with some purine and pyrimidine bases and nucleosides

A study of the reactions of purine and pyrimidine bases has been initiated with the V(IV) complex [V(O)(acac)₂]. Two distinct modes of reaction have been recognized depending on the nature of the base. Simple adduct formation occurs when the base contains a sufficiently basic lone pair, but when bases contain acidic protons bound to nitrogen (inosine, thymine), cleavage of one acetylacetonate ligand occurs to give potentially polymeric species. This behavior is in contrast to that of the inert [Co(NO₂)₂(acac)₂]⁻ ion.     

Thiocarbonyl, thiocarbyne and thiocarbene ligands in di- and polynuclear complexes

Thiocarbonyl (CS), homologous to the ubiquitous carbonyl ligand, has interesting and unique properties as ligand. Nevertheless it did not reach the widespread use of CO in the formation of transition metal complexes. This short account, dedicated to professor R.J. Angelici, is focused on the multisite coordination of thiocarbonyl ligand in di- and poly-nuclear transition metal complexes, and to its transformation into thiocarbyne and thiocarbene ligands. These latter, in turn, can be transformed, providing access to a variety of new ligands and functionalities, which are here briefly reviewed.     

Design,Analysis, and Characterization of Designer Surface Plasmon Polariton-Based Dual-Band Antenna

This paper reports development, design, and analysis of designer (or spoof) surface plasmon polariton-based feeding configuration to excite a dual-band antenna. As an example, a planar transverse electric and magnetic horn antenna is designed and fed by the proposed transition structure. Designer surface plasmon polariton modes are supported by a metal surface at microwave frequency when it is corrugated with periodical grooves. An efficient transition for converting quasi-transverse electric and magnetic waves of microstrip line into spoof surface plasmon polariton (SSPP) waves has been designed in microwave frequency range using periodically corrugated metal strip. SSPP wave is confined at the teeth part of the corrugation. Simulated and measured reflection and transmission characteristics are in good agreement. The spoof SPP-fed dual-band antenna is designed, fabricated, and characterized in microwave anechoic chamber and measured results are coincident with simulated results.     

Metalloproteomics, metalloproteomes, and the annotation of metalloproteins

Metalloproteomics includes approaches that address the expression of metalloproteins and their changes in biological time and space. Metalloproteomes are investigated by a combination of approaches. Experimental approaches include structural genomics, which provides insights into the architecture of metal-binding sites in metalloproteins and establishes ligand signatures from the types and spacings of the metal ligands in the protein sequence. Theoretical approaches employ these ligand signatures as templates for homology searches in sequence databases. In this way, the number of metalloproteins in the iron, copper, and zinc metalloproteomes in various phyla of life has been estimated. Yet, manganese metalloproteomes remain poorly defined. Metals have catalytic and structural functions in proteins. However, additional functions have evolved. Proteins that control metal homeostasis and proteins that are metal-regulated bind metal ions transiently and are generally not accounted for in estimates from bioinformatics. Thus, metalloproteomes are dynamic and likely to be larger than present estimates suggest. This account discusses the assignment of transition metals in metalloproteins and the ensuing issues facing analytical chemists and structural and computational biologists. Biological and chemical selectivities render metal selection by metalloproteins either more stringent or less stringent depending on the metal homeostatic system of the organism, the subcellular location of the protein, and environmental factors. Failure to recognize the principles of metal utilization has led to assigning the wrong metal in metalloproteins and has missed some of the regulatory functions of transition metal ions.     

Reactivity of Al(III) with membrane phospholipids: a NMR approach

The complexes Al(acac)₃ (1) (acac = 2,4-pentanedionate) and Al(malt)₃ (malt = 3-hydroxy-2-methyl-4-pyronate) (2) react with dl--dipalmitoylphosphatidylcholine (DPPC) under a 1:1 molar ratio in CDCl₃ at 37 °C, as shown by the substantial release of ligands (20–50%) from the metal coordination sphere (¹H-NMR), by evident changes in the ¹H-NMR spectrum of DPPC in the reaction mixture and by the appearance of a ³¹P-NMR signal due to metal-coordinated DPPC. ³¹P-NMR spectra reveal that both 1 and 2 also react with DPPC in water, in the presence of 1% Triton X-100 and Tris buffer. Under these conditions, 1 and 2 do not react with ghosts from human erythrocytes. On the contrary, the far less hydrolytically stable complex Al(lact)₃ (lact = lactate) appears to be reactive under identical conditions, as shown by ³¹P-NMR spectra.