Pentacopper(II) complexes of alpha-aminohydroxamic acids: uranyl-induced conversion of a 12-metallacrown-4 to a 15-metallacrown-5

Effects of uranyl on the pentacopper(II) complexes of alpha-leucinehydroxamic acid and alpha-tyrosinehydroxamic acid were studied in water and methanol by means of electrospray ionisation mass spectrometry (ES-MS), absorption spectrophotometry, circular dichroism spectroscopy and proton NMR spectroscopy. All the measurements were consistent with the complete conversion of a 12-metallacrown-4 to a 15-metallacrown-5 upon addition of one equivalent of the uranyl ion. The uranyl ion is accommodated in the cavity formed by five copper(II) ions and five alpha-aminohydroxamate ligands. The 15-metallacrown-5 inclusion complexes have a high affinity for the uranyl ion. Competition studies showed that even in the presence of a large excess of calcium(II), the 15-metallacrown-5 remained stable, and no exchange reactions between calcium(II) and uranyl were observed. Extraction of uranyl from the 15-metallacrown-5 was also not detected in the presence of a large excess of 18-crown-6. Trivalent lanthanide ions can be partially sequestered by the 15-metallacrown-5, however, even these trivalent ions are displaced by uranyl.     

Succinylhydroxamic derivatives of alpha-amino acids as MMP inhibitors. Study of complex-formation equilibria with Cu2+, Ni2+ and Zn2+

A series of Pro- and Phe-succinyl hydroxamate derivatives, whose nanomolar inhibitory activity towards a series of matrix metalloproteinases (MMPs) was previously reported, have been studied and described herein in their interaction with Cu(2+), Zn(2+), Ni(2+) in aqueous solution, by using potentiometric, spectroscopic and ESI-MS (electrospray ionization mass) spectrometric techniques. A systematic study at various ligand-to-metal molar ratios allowed the determination of the stability constants of the complexes as well as the estimation of the coordination modes. The similarity in the biological activity of these compounds seems to be paralleled by the identical metal-complexation behaviour at neutral pH, namely in terms of chelating effectiveness and coordination modes, irrespective of the presence of one carboxylic or hydroxamate as extra groups, or also of the type of amino-acid residue at the other flank of the succinyl chain, which seems to be enough away from the succinyl hydroxamate metal-binding group. The stability order of the metal complexes with these ligands follows the Irving-Williams trend for this type of complex systems. Noteworthy is the identification of an interesting pentanuclear copper(II) species with the monohydroxamic ligands which structure was ascribed to a 12-metallacrown-4.     

Copper(II) complexes of some N-substituted bis(aminomethyl)phosphinate ligands. An integrated EPR study of microspeciation and coordination modes by the two-dimensional simulation method

Copper(II) complexes of bis(aminomethyl)phosphinic acid (L1), bis(N-glycino-N-methyl)phosphinic acid (L2), bis(N-benzylglycino-N-methyl)phosphinic acid (L3), bis(l-prolino-N-methyl)phosphinic acid (L4) and bis(iminodicarboxymethyl-N-methyl)phosphinic acid (L5) were studied in aqueous solution by pH-potentiometric and electron paramagnetic resonance (EPR) spectroscopic methods. The EPR spectrum packages recorded at various ligand-to-metal concentration ratios and pH's were analyzed (after matrix rank analysis by the method of residual intensities as a complementary method) by the two-dimensional computer simulation method, which simultaneously determines the formation constants and the EPR parameters of the various (micro)species. L1 forms mono and bis complexes in different protonation states; for the other ligands, the mono complexes are always prevalent. For steric reasons, the formation of CuL is shifted to increasingly higher pH regions in the sequence L2, L3 and L4. CuLH was identified for L3, L4 and L5, and also CuLH(2) for L4 and L5. Cu(2)L(2) was found in small amounts for L3 and L4, while it predominates at pH>4 for L5. For L5, Cu(2)L(2)H(2) was also detected. For the ligands that form dimeric metal complexes in equimolar solution or at a ligand excess, Cu(2)L is formed at a metal ion excess. Ligation of the phosphinate O was suggested by indirect proofs in the protonated complexes of L1. For the ligands L2, L3 and L4, the copper(II) coordination in various species in different protonation states is reminiscent of that in the mono and bis complexes of simple amino acids. For the bis(aminomethyl)phosphinates, however, the cis positions of the amino groups in CuL are ensured by the structure of the ligand, and the isomers differ from each other in the (equatorial or axial) position of the second carboxylate group.     

Transition Metal Complexes of 5-Amino-1-β-D-Ribofuranosylimidazole-4-Carboxylic Acid 5′-Phosphate,an Intermediate in the de novo Biosynthesis of Purine Nucleotides: Synthesis and Effects on Enzyme Activity

Abstract

Transition metal complexes [Cu(II), Co(I1) and Ni(II)] of 5-amino-l-β-D-ribofuranosylimidazole-4-carboxylic acid have been prepared and shown to form a series of stoichiometry ML₂, nM(OH₂) (n = 0,1,2) and structures have been assigned. Analogous complexes of 5-amino-l-β-D-ribofuranosylimidazole-4-carboxy1ic acid 5′-phosphate (CAIR), a central intermediate in the de novo pathway to purine nucleotides, produced in aqueous solution have been found to affect the activity of the enzyme AIR- carboxylase (E.C. 4.1.1.21).     

Copper complexes immobilized to chitosan.

Polymeric ligands, such as 2-substituted pentanedioic acid (2), 2-substituted propanoic acid (3), and deoxylactit-1-yl (4) derivatives of chitosan (1), were used to prepare copper complexes that are widely soluble in aqueous solution. EPR results (100 K) show that all association complexes basically have a tetragonal symmetry. Visible CD spectra suggest, however, that the order of increasing departure from this geometry is Cu-(1) approximately Cu-(3) less than Cu-(2) less than or equal to Cu-(4), the lack of sterically constraining side-chains in (1) and (3) allowing a more symmetric arrangement of ligands around the central metal ion. Results on the catalytic activity of the association complexes for air oxidation of catechol derivatives are also presented.     

Effect of pressure on the helix and random coil forms of poly(D-glutamic acid)

The absorption spectrum of the aqueous solution of acridine orange (AO)-poly–(D -glutamic acid) (PDGA) complex at pH 4.5 (helix form) did not show any wavelength shift, but at pH 7.5 (coil form) changed to the absorption curve of the helix form by compression up to 4500 atm. The ionization degree of PDGA estimated from the electric conductivity of the aqueous solution of PDGA at 4500 atm. was a value of about 5.3%. The entropy of the helix formation of PDGA from the titration data at 1 atm. and 30°C. was negative ?2.98 e.u. It will be concluded in this report that the volume change for coil to helix could be positive for PDGA and negative for AO–PDGA complexes.     

Aqueous and solid complexes of iron(III) with hyaluronic acid. Potentiometric titrations and infrared spectroscopy studies

The coordination of iron(III) ion to hyaluronic acid (Hyal) in aqueous solutions and solid state was accomplished by potentiometric titrations and infrared spectroscopy. The potentiometric titration studies provided the binding constants for the complexes found in the systems and the speciation of these species according to the variation of pH values. The complexes found presented a complexing ability through both the chelating moieties of Hyal (via the N-glucosamine and D-glucoronic acid), showing no special preference for either one while in solid state, but when in aqueous solution the complexation via the N-glucosamine moiety was the preferred, forming two complexed species, ML and ML(2) (log K(ML)=8.2 and log K(ML2)=7.9). The presence of a mu-oxo complex via the D-glucoronic acid was also detected in both aqueous (log K=6.7) and solid states via the N-glucosamine and D-glucoronic acid simultaneously linked to two Hyal chains. A structure for this latter complex was suggested. The results indicated that these complexes could be used in eliminating the excess iron(III) in living organisms.     

A comparative analysis of the interaction of borate ion with various polyols.

Although it is now generally accepted that borate ion, B(OH)₄^?, reacts with suitable polyols in aqueous solution to form two types of complexes with strongly acidic properties (1), several investigators have presented evidence to show the formation of two types of complexes is stoichiometrically unsatisfactory (2,3).Aside from its usefulness in structural studies, the reaction has important implications in numerous biochemical applications. Many compounds of biological importance contain hydroxyl groups in positions favorable for reaction with borate ion.As an extension of previous work (4) we report here the determination of solution stability constants of borate ion complexes with several biologically important polyols by means of a pH method and in two instances a calorimetric method.     

Effect of pH on complex formation between debranched waxy rice starch and fatty acids

Complex formations between debranched waxy rice starch (DBS) and fatty acids (FA) of different hydrocarbon chain lengths (8:0, 10:0, 12:0, 14:0, 16:0, and 18:0) were studied in an aqueous solution by measuring the blue colour stained with iodine. The objective of this study was to understand the effects of the solubility and hydrophobicity of guest molecules (FA) on the complex formation with DBS. Lauric acid (12:0) displayed the greatest complex forming ability with DBS by showing the least blue colour developed with iodine. The effect of pH (3-7) on the DBS/FA complex formation was evaluated by measuring the iodine-scanning spectra of the mixture. Short-chain FA (8:0) displayed less complex formation at pH>or=5, above the pK(a) of fatty acid (approximately 4.8), which suggested that the charge formation of the short-chain FA caused a lower partitioning of the FA into the hydrophobic cavity of the DBS single helix. On the contrary, FA of 10:0-18:0 displayed an increased complex formation at pH>5, which could be attributed to increased solubility of these longer-chain FA at a dissociated and ionized form. The hydrocarbon chain length of the FA had an important impact on the extent of the complex formation. A FA that had a shorter hydrocarbon chain was more soluble in an aqueous solution and more readily formed a complex with DBS. At pH 6 and 7 (above the pK(a)), 10:0 formed less inclusion complexes with DBS than did 12:0. Iodine-scanning spectra showed that the absorbances of all iodine-stained DBS/FA solutions at higher wavelength were substantially lower than that of the iodine-stained DBS alone, suggesting that FA preferentially formed inclusion complexes with DBS of longer chains.     

The lactam of alpha-guanidinoglutaric acid (1-amidino-2-pyrrolidone-5-carboxylic acid)

alpha-Guanidinoglutaric acid (alpha-GGA) has been reported to occur in the cerebral cortex after epileptic seizures. No physical characteristics of alpha-GGA have been given. A practical procedure for the preparation of alpha-GGA is reported here. alpha-GGA forms a lactam in aqueous solution at 80 degrees C. It is proposed to substitute this lactam, 1-amidino-2-pyrrolidone-5-carboxylic acid (pAGlu), for pyroglutamic acid (pGlu) at the N-terminal position in neuropeptides to modify their biological characteristics. L(+)-Glutamic acid was reacted with S-methylisothiourea (I) at pH 10 in aqueous solution to form L(-)-alpha-guanidinoglutaric acid: mp 165-168 degrees C, [alpha]22D = -22.7 (C = 4, 2 M HCl). alpha-GGA reacted promptly with excess reagent to form a salt, S-methylisothiourea-alpha-guanidinoglutarate: mp 209-210 degrees C, [alpha]22D = -13.0 (C = 4, 2 M HCl). I was removed from the salt with aqueous picric acid, since I readily formed an insoluble picrate, S-methylisothiourea picrate (mp 225-228 degrees C). Alternatively, the salt was added to a cation exchange column, and the alpha-GGA was eluted with molar ammonium acetate buffer, pH 9.5. Its lactam, 1-amidino-2-pyrrolidone-5-carboxylic acid, mp 248-249 degrees C, [alpha]22D = +2.1 (C = 4, 2 M HCl), formed a picrate (mp 196-199 degrees C).     

Chitosan-Based Mucoadhesive Systems for the Inclusion of the Echinochrome Active Substance

Polyelectrolyte complexes (PECs) of chitosan (CH) with kappa/beta carrageenan (κ/β-K), a polysaccharide of red algae, were obtained in a soluble form and as films. Using porcine intestinal mucosa as a model, it was shown that single-layer films obtained from polysaccharides and a three-layer film containing their polyelectrolyte complex exhibited mucoadhesive properties. The mucoadhesive ability of the films depended on the polysaccharide type and changed after PEC formation. Comparative analysis of the ζ-potential values determined for the soluble form of polyelectrolyte complexes in an aqueous solution and in a mucin-containing solution confirmed the mucoadhesive properties of the PECs. It was found that the complexes retained their mucoadhesive properties upon the inclusion of echinochrome A in their soluble form. This made it possible to consider them noninvasive forms of drug delivery.     

Interaction of taxol with human serum albumin

Taxol (paclitaxel) is an anticancer drug, which interacts with microtuble proteins, in a manner that catalyzes their formation from tubulin and stabilizes the resulting structures (Nogales et al., Nature 375 (1995) 424-427). This study was designed to examine the interaction of taxol with human serum albumin (HSA) in aqueous solution at physiological pH with drug concentrations of 0.0001-0.1 mM, and HSA (fatty acid free) concentration of 2% w/v. Gel electrophoresis, absorption spectra and Fourier transform infrared (FTIR) spectroscopy with self-deconvolution and second-derivative resolution enhancement were used to determine the drug binding mode, binding constant and the protein secondary structure in the presence of taxol in aqueous solution. Spectroscopic evidence showed that taxol-protein interaction results into two types of drug-HSA complexes with overall binding constant of K=1.43 x 10(4) M(-1). The molar ratios of complexes were of taxol/HSA 30/1 (30 mM taxol) and 90/1 (90 mM taxol) with the complex ratios of 1.9 and 3.4 drug molecules per HSA molecule, respectively. The taxol binding results in major protein secondary structural changes from that of the alpha-helix 55 to 45% and beta-sheet 22 to 26%, beta-anti 12 to 15% and turn 11 to 16%, in the taxol-HSA complexes. The observed spectral changes indicate a partial unfolding of the protein structure, in the presence of taxol in aqueous solution.     

Interactions of atrazine and 2,4-D with human serum albumin studied by gel and capillary electrophoresis, and FTIR spectroscopy.

The herbicides 6-chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine (atrazine) and 2,4-dichlorophenoxyacetic acid (2,4-D) are widely used in agricultural practice to fight dicotyledon weeds mainly in maize, cereals, and lucerne. As a result, these compounds are found not only in the plants, soil, and water, but also in the cultivated ground in the following years as well as in agricultural products such as fruits, milk, butter, and sugar beet. The toxicological effects of herbicides occur in vivo, when transported to the target organ through the bloodstream. It has been suggested that human serum albumin (HSA) serves as a carrier protein to transport 2,4-D to molecular targets. This study was designed to examine the interaction of atrazine and 2,4-D with HSA in aqueous solution at physiological pH with herbicide concentrations of 0.0001-1 mM, and final protein concentration of 1% w/v. Gel and capillary electrophoresis, UV-visible and Fourier transform infrared spectroscopic methods were used to determine the drug binding mode, the drug binding constant, and the protein secondary structure in aqueous solution. Structural analysis showed that different types of herbicide-HSA complexes are formed with stoichiometric ratios (drug/protein) of 3:1 and 11:1 for atrazine and 4.5:1 and 10:1 for 2,4-D complexes. Atrazine showed a weak binding affinity (K=3.50 x 10(4) M(-1)), whereas two bindings (K(1)=2.50 x 10(4) M(-1) and K(2)=8.0 x 10(3) M(-1)) were observed for 2,4-D complexes. The herbicide binding results in major protein secondary structural changes from that of the alpha-helix 55% to 45--39% and beta-sheet 22% to 24--32%, beta-anti 12% to 10--22% and turn 11% to 12--15%, in the drug-HSA complexes. The observed spectral changes indicate a partial unfolding of the protein structure, in the presence of herbicides in aqueous solution.     

Iminodiacetyl-hydroxamate derivatives as metalloproteinase inhibitors: equilibrium complexation studies with Cu(II), Zn(II) and Ni(II)

Two new iminodiacetyl-hydroxamate derivatives, the N-benzyl-N-carboxymethyl-iminoacetohydroxamic acid (H(2)L(1)) and the N-benzyl-N'-hydroxypiperazine-2,6-dione (HL(2)), have been recently reported as very effective inhibitors against a set of zinc-containing matrix metalloproteinases (MMPs). Herein, aimed at understanding that inhibitory function, these compounds are studied in their complex formation equilibria with three biologically relevant first-row transition M(2+) metal ions (M=Cu, Zn, Ni) by using potentiometric and spectroscopic techniques. At physiological conditions, complexation of these metal ions by H(2)L(1) mostly occurs with formation of 1:1 species by tridentate co-ordination (O,N,N) (carboxylate-amino-hydroxamate), whereas complexation with HL(2) mainly involves the formation of 1:2 (M:L) species with normal (O,O) hydroxamate coordination. Moreover, at higher pH, H(2)L(1) is able to form a pentanuclear tetrameric copper complex with an interesting 12-metallacrown-4 structure.     

Synthesis, characterization and anti-tumour testing of some platinum(II) amine complexes containing 1,1- and 1,2-cyclobutanedicarboxylate ligands

A series of new platinum(II) amine complexes containing 1,1- and 1,2-cyclobutanedicarboxylate ligands, cis-[PtA2(1,1-CBDCA)] (A = RNH2, where R = C2H5, n-C3H7, n-C4H9, n-C5H11, n-C6H13, c-C3H5, c-C5H9, c-C6H11; A2 = ethylenediamine, 1,3-diaminopropane), cis-[PtA2(1,2-CBDCA)] (A = NH3, RNH2 where R = CH3, C2H5, n-C3H7, n-C4H9, c-C3H5) and trans-[Pt(NH3)2(1,1-CBDCAH)2] (CBDCA, CBDCAH = dianion and monoanion of the dicarboxylic acid, respectively) have been synthesized by an improved route. These complexes are stable in aqueous solution and show good aqueous solubility. The [Pt(c-C3H5NH2)2(1,1-CBDCA)] can be isolated in white, grey and blue forms. The grey and blue forms exhibit ESR signals analogous to the so-called platinum blues. The existence of the blue form in aqueous solution is time and temperature dependent. Several of the complexes have been tested against leukaemia L1210 in male BDF mice and activity appears to decrease with the increase in length of the aliphatic chain (or increase in size of the alicyclic ring) of the primary amine. The Yoshida lymphoscarcoma screen, usually insensitive to platinum drugs, was found to respond well to [Pt(n-C4H9NH2)2(1,1-CBDCA)] in 5-day subcutaneously implanted tumours in female Wistar rats.     

Carbon-13 magnetic resonance spectra of nucleosides and their Pd(II) complexes.

Chemical shifts occurring in carbon-13 magnetic resonance spectroscopy are utilized to assess the site of complexation of nucleosides to enPdC12 in neutral aqueous solutions. Binding occurs at N3 in cytidine, thymidine, and uridien, at N7 in 1-methylguanosine, and at N1 in guanosine. For most carbon atoms adjacent to N3 in the pyrimidine nucleosides the complexation shifts of the basic ligand are about 30% of the corresponding upfield protonation shifts. All complexes are of the form enPdL2 indicating that the ligands are unidentate and that the tendency to chelation is weak. Carbon-13 magnetic resonance spectroscopy appears to be the best method for delineating these complexes in solution. Due to the high avidity of chloride ion for Pt(II), cis dichloro Pd(II) complexes may be better models for intracellular action of the corresponding Pt(II) complexes than the Pt(II) complexes themselves.     

Synthesis, spectroscopic characterization and biological activity on newly synthesized copper(II) and nickel(II) complexes incorporating bidentate oxygen-nitrogen hydrazone ligands

We report the synthesis of the hydrazone ligands, 1-(phenyl-hydrazono)-propan-2-one (PHP), 1-(p-tolyl-hydrazono)-propan-2-one (THP), 1-[(4-chloro-hydrazono)]-propan-2-one (CHP), and their Ni(II) and Cu(II) metal complexes. The structure of the ligands and their complexes were investigated using elemental analysis, magnetic susceptibility, molar conductance and spectral (IR, UV, and EPR) measurements. IR spectra indicate that the free ligands exist in the hydrazo-ketone rather than azo-enol form in the solid state. Also, the hydrazo-NH exists as hydrogen bonded to the keto-oxygen either as intra or as intermolecular hydrogen bonding. In all the studied complexes, all ligands behave as a neutral bidentate ligands with coordination involving the hydrazone-nitrogen and the keto-oxygen atoms. The magnetic and spectral data indicate a square planar geometry for Cu²⁺ complexes and an octahedral geometry for Ni²⁺ complexes. The ligands and their metal chelates have been screened for their antimicrobial activities using the disc diffusion method against the selected bacteria and fungi. They were found to be more active against Gram-positive than Gram-negative bacteria. It may be concluded that the antimicrobial activity of the compounds is related to cell wall structure of bacteria.Protonation constant of (PHP) ligand and stability constants of its Cu²⁺ and Ni²⁺ complexes were determined by potentiometric titration method in aqueous solution at ionic strength of 0.1 M sodium nitrate. It has been observed that the hydrazone ligand (PHP) titrated here has one protonation constant. The divalent metal ions Cu²⁺ and Ni²⁺ form with (PHP) 1:1 and 1:2 complexes. The insolubility of (THP) and (CHP) ligands in aqueous medium does not permit the determination of their protonation constants and formation constants of the corresponding complexes in aqueous solution.     

DNA aqueous solution used for dialytical removal and enrichment of dioxin derivatives

In the present study, a dialytic method that uses a DNA aqueous solution to remove and enrich dioxins from polluted water was proposed. Circular dichroism (CD) and fluorescent spectra indicated that dibenzo-p-dioxin (DD), dibenzofuran (DF) and biphenyl (BP), which are dioxin derivatives, form complexes with DNA. Their experimental dialytic sorption coefficients were measured by quantifying the concentrations of DD, DF, and BP in aqueous solutions before and after dialysis of the DNA solution, and the values were 2.1×10⁵, 1.3×10⁵, and 1.5×10⁷, respectively. As a simulated water treatment model, DNA solution was dialyzed in an aqueous mixture of DD, DF, and BP for 96 h, the HPLC studies showed that the dioxin derivatives have been concentrated in the DNA solution about 200 times. The dialyzed DNA solution was reusable by an extraction with hexane.     

Cycloamylose complexation of adamantane derivatives

Spectrophotometric and pH potentiometric studies indicate that cyclohexaamylose (alpha-cyclodextrin) and cycloheptaamylose (beta-cyclodextrin) form aqueous complexes with all adamantane derivatives examined to date. Thermodynamic complex formation constants are reported for the substrates 1-adamantaneamine (amantadine), 1-adamantaneammonium ion, 1-adamantanemethylamine, 1-adamantane-methylammonium ion, 1-adamantanecarboxylic acid, 1-adamantane-carboxylate ion, 1-adamantaneacetic acid and 1-adamantaneacetate ion. The existence of these complexes implies that cycloamylose might serve as a therapeutic sequestering agent for adamantane derivatives.     

Metal complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid and benzohydroxamic acid. Crystal and molecular structure of [Cu(phen)2(Cl)]Cl x H2Sha, a model for a peroxidase-inhibitor complex

Stability constants of iron(III), copper(II), nickel(II) and zinc(II) complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid (HAha) and benzohydroxamic acid (HBha) have been determined at 25.0 degrees C, I=0.2 mol dm(-3) KCl in aqueous solution. The complex stability order, iron(III) > copper(II) > nickel(II) approximately = zinc(II) was observed whilst complexes of H2Sha were found to be more stable than those of the other two ligands. In the preparation of ternary metal ion complexes of these ligands and 1,10-phenanthroline (phen) the crystalline complex [Cu(phen)2(Cl)]Cl x H2Sha was obtained and its crystal structure determined. This complex is a model for hydroxamate-peroxidase inhibitor interactions.