Glass Electrode Potentiometry Research Articles

Thermodynamic evaluation of the stability of the bone-seeking radiopharmaceutical [177Lu]Lu(III)–DOTP under simulated blood plasma conditions

The stability and in vivo robustness of [177Lu]Lu–DOTP as a potential bone-targeting radiopharmaceutical was determined with the aid of thermodynamic blood plasma modeling simulations. Glass electrode potentiometry was employed to measure the stability constants of the complexes of Lu3+ with DOTP. Similarly, the complexes of DOTP with a selection of the important physiological metal ions: Ca2+, Mg2+, and Cu2+ were determined, representing the typical interactions that the ligand would encounter upon administration. This made possible the construction of a blood plasma model of DOTP, aiding in establishing the potential susceptibility of the radiopharmaceutical. The ligand binds predominantly to calcium in vivo, accounting for 59.6% of that initially introduced as a component of the Lu–DOTP complex. Furthermore, due to a preference of the DOTP to bind to Cu2+ it causes mobilization of the ions in blood plasma, and would therefore indicate a deficiency if the ligand is administered at a concentration of 8.5×10−5moldm−3. The lutetium-ions are preferentially bound to DOTP, with as much as 98.1% of the Lu3+ occupying the ligand under physiological conditions.

Complexation of 1,3-Bis(tris(hydroxymethyl)methylamino)propane Systems Involving Divalent (Cobalt, Nickel, or Zinc) Ions in Aqueous Solution by Potentiometry

Protonation constants of 1,3-bis(tris(hydroxymethyl)methylamino)propane (BTP) and the complexes formed between BTP and Co(II), Ni(II), or Zn(II) metal ions have been studied by glass electrode potentiometry (GEP) in aqueous 0.1 mol·L–1 KNO3 supporting electrolyte at 25 ± 0.1 °C. The complexation model for each M(II)–BTP system was established. The proposed final model for Ni(II)–BTP system is: NiL, NiLH–1, and NiLH–2, with stability constant values, as log β, of 7.13 ± 0.02, −1.32 ± 0.04, and −10.81 ± 0.05, respectively. For Co(II)–BTP and Zn(II)–BTP systems, the proposed final model is constituted by ML, ML2, ML2H–1, and ML2H–2 complexes. For the Co(II)–BTP system, the overall refined stability constants (as log β) are 4.57 ± 0.02, 8.76 ± 0.02, 0.17 ± 0.03, and −8.73 ± 0.03, respectively, and for Zn(II)–BTP system they are 4.99 ± 0.02, 9.18 ± 0.03, 1.01 ± 0.03, and −7.91 ± 0.04, respectively. In a general way, the complex stability was found to follow the trend: Ni(II) > Zn(II) > Co(II).

Cadmium(II), Lead(II), and Zinc(II) Ions Coordination ofN,N′-(S,S)Bis[1-carboxy-2-(imidazol-4yl)ethyl]ethylenediamine: Equilibrium and Structural Studies

The binding ability of cadmium(II), lead(II), and zinc(II) with N,N′-(S,S)bis[1-carboxy-2-(imidazol-4yl)ethyl]ethylenediamine (BCIEE) and the structure of the formed complexes have been investigated, in aqueous solution, by potentiometry and 1H NMR and 13C NMR spectroscopy for the first time. Stability constants for the cadmium, lead, and zinc complexes with BCIEE were studied by glass electrode potentiometry (GEP) at a fixed total ligand to total metal concentration ratios, varied pH values at (25.0 ± 0.1) °C, and an ionic strength of 0.1 M KCl. For the Cd-BCIEE and Pb-BCIEE systems, three species, MH2L, MHL, and ML, were identified. For the Cd-BCIEE system, the overall stability constants values are 20.63 ± 0.02, 14.78 ± 0.01, and 8.22 ± 0.02, respectively. For the Pb-BCIEE system, the overall stability constants values are 19.71 ± 0.02, 13.78 ± 0.02, and 6.63 ± 0.02, respectively. For the Zn-BCIEE system, two species, ZnH2L and ZnL, were identified, and the overall stability constants values are 21.84 ...

Sequestering Ability of Dicarboxylic Ligands Towards Dioxouranium(VI) in NaCl and KNO3 Aqueous Solutions at T=298.15 K

The formation constants of dioxouranium(VI)-2,2′-oxydiacetic acid (diglycolic acid, ODA) and 3,6,9-trioxaundecanedioic acid (diethylenetrioxydiacetic acid, TODA) complexes were determined in NaCl (0.1≤I≤1.0 mol⋅L−1) and KNO3 (I=0.1 mol⋅L−1) aqueous solutions at T=298.15 K by ISE-[H+] glass electrode potentiometry and visible spectrophotometry. Quite different speciation models were obtained for the systems investigated, namely: ML0, MLOH−, ML22−, M2L2(OH)−, and M2L2(OH)22−, for the dioxouranium(VI)–ODA system, and ML0, MLH+, and MLOH− for the dioxouranium(VI)–TODA system (M=UO22+ and L = ODA or TODA), respectively. The dependence on ionic strength of the protonation constants of ODA and TODA and of both metal-ligand complexes was investigated using the SIT (Specific Ion Interaction Theory) approach. Formation constants at infinite dilution are [for the generic equilibrium pUO22++q(L2−)+rH+⇌(UO22+)p(L)qHr(2p−2q+r);βpqr]: log 10β110=6.146, log 10β11−1=0.196, log 10β120=8.360, log 10β22−1=8.966, log 10β22−2=3.529, for the dioxouranium(VI)–ODA system and log β110=3.636, log 10β111=6.650, log 10β11−1=−1.242 for dioxouranium(VI)–TODA system. The influence of etheric oxygen(s) on the interaction towards the metal ion was discussed, and this effect was quantified by means of a sigmoid Boltzman type equation that allows definition of a quantitative parameter (pL50) that expresses the sequestering capacity of ODA and TODA towards UO22+; a comparison with other dicarboxylates was made. A visible absorption spectrum for each complex reaching a significant percentage of formation in solution (KNO3 medium) has been calculated to better characterize the compounds found by pH-metric refinement.

Blood plasma model predictions for the proposed bone-seeking radiopharmaceutical [117mSn]Sn(IV)-N,N′,N′-trimethylenephosphonate-poly(ethyleneimine)

In an attempt to elucidate the in vivo stability of the prospective radiopharmaceutical [(117m)Sn]Sn(IV)-PEI-MP, where PEI-MP stands for N,N',N'-trimethylenephosphonate-polyethyleneimine, glass electrode potentiometry was used to determine the stability constants of the Sn(4+) ion as complexed with a variety of physiological amino acids. In addition, linear free energy relationship (LFER) correlation plots were used to extrapolate the constants of the major blood plasma ligands, based on data from Cu(2+), Pb(2+), and Zn(2+). In so doing, a thermodynamic model of blood plasma was established for Sn(4+) from which the complexation tendencies of Sn(4+) were predicted in the event of the intravenous administration of such a drug. It was found that the Sn(IV)-PEI-MP could succumb to competition by the glutamine amino acid, which forms more stable complex(es), whilst the PEI-MP gets taken up largely by Ca(2+). Also, this study shows the value of the in vitro experiments and modeling performed for radiopharmaceutical research and for attempts to reduce the number of animal experiments.

Potentiometric and spectroscopic studies on the solution molecular structures of copper(II)-[S]-2-[N-(2′-hydroxybenzyl)aminomethyl]pyrrolidine complexes, potential non-steroidal anti-inflammatory agents (NSAIDs)

The purpose of this study was to investigate the complexes formed by copper(II) with potential non-steroidal anti-inflammatory agents (NSAIDs) under physiological conditions. A former study suggested that 2-benzylaminomethylpyrrolidine ligands could be good candidates as potential OIL ( OH-inactivating ligand) when complexed to copper(II). In order to assess the chemical behavior as OIL, [S]-2-[N-(2′-hydroxybenzyl)aminomethyl]pyrrolidine (OHbamp) was synthesized and bound to copper(II). Physico-chemical properties were determined at 37 °C in 0.15 M NaCl using glass electrode potentiometry, UV–Vis and circular dichroism spectroscopies, before and after copper(II) complexation. [Cu(OHbamp)(H 2O) 3] + was the main complex found at both physiological and inflammatory pH values, showing appreciable stability at pathological pH compared to copper(II) complexes of histidine, the predominant low-molar-mass ligand of copper(II) in blood plasma. However, neutral species such as [Cu(OHbamp) 2(H 2O) 2] and [Cu(OHbamp)(OH)(H 2O) 3] are predominant only above pH 8, preventing a significant amount of drug from diffusing through membranes at inflammatory pH. In conclusion, copper(II)-OHbamp system does not meet all the requirements to be an OIL. Nevertheless, these results allow us to better identify the chemical features needed for a good OIL candidate.

Spectroscopic study of protonation of oligonucleotides containing adenine and cytosine

AbstractAcidobasic properties of purine and pyrimidine bases (adenine, cytosine) and relevant nucleosides (adenosine, cytidine) were studied by means of glass-electrode potentiometry and the respective dissociation constants were determined under given experimental conditions (I = 0.1 M (NaCl), t = (25.0 ± 0.1) °C): adenine (pK HL = 9.65 ± 0.04, pK H2L = 4.18 ± 0.04), adenosine (pK H2L = 3.59 ± 0.05), cytosine (pK H2L = 4.56 ± 0.01), cytidine (pK H2L = 4.16 ± 0.02). In addition, thermodynamic parameters for bases: adenine (ΔH 0 = (−17 ± 4) kJ mol−1, ΔS 0 = (23 ± 13) J K−1 mol−1), cytosine (ΔH 0 = (−22 ± 1) kJ mol−1, ΔS 0 = (13 ± 5) J K−1 mol−1) were calculated. Acidobasic behavior of oligonucleotides (5′CAC-CAC-CAC3′ = (CAC)3, 5′AAA-CCC-CCC3′ = A3C6, 5′CCC-AAA-CCC3′ = C3A3C3) was studied under the same experimental conditions by molecular absorption spectroscopy. pH-dependent spectral datasets were analyzed by means of advanced chemometric techniques (EFA, MCR-ALS) and the presence of hemiprotonated species concerning (C+-C) a non-canonical pair (i-motif) in titled oligonucleotides was proposed in order to explain experimental data obtained according to literature.

In vitro and in vivo studies of the dermally absorbed Cu(II) complexes of N 5O 2 donor ligands – Potential anti-inflammatory drugs

Copper complexes of N, N′-di(aminoethylene)-2,6-pyridinedicarbonylamine and bis-( N, N-dimethylethyl)-2,6-pyridinedicarboxamide have been studied by glass electrode potentiometry, NMR, UV and IR spectroscopy as potential anti-inflammatory agents for the alleviation of inflammation associated with rheumatoid arthritis. The protonation and formation constants with Cu(II), Zn(II) and Ca(II), determined at 25 °C and an ionic strength of 0.15 mol dm −3 were used to calculate the copper plasma mobilizing index of the ligands. Spectroscopic studies suggested that metal ion complexation promotes deprotonation and coordination of the amide nitrogens resulting in overall tetragonal distorted copper complexes. Bio-distribution and dermal absorption studies showed the complexes to have relatively long biological half-lives with 50% of the injected dose remaining in the body 24 h after administration.

Complexation of M–(buffer) x –(OH) y Systems Involving Divalent Ions (Cobalt or Nickel) and Zwitterionic Biological Buffers (AMPSO, DIPSO, TAPS and TAPSO) in Aqueous Solution

The complexation behavior of eight M–(buffer) x –(OH) y systems involving two divalent ions (cobalt and nickel) and four zwitterionic biological buffers (AMPSO, DIPSO, TAPS and TAPSO) were characterized. Complex formation was detected for all eight M–(buffer) x –(OH) y systems studied, but fully defined final models were obtained for only four of these systems. For systems involving cobalt or nickel with AMPSO or TAPS, a complete characterization of the systems was not possible in the studied buffer pH-range. Metal complexation was studied by glass-electrode potentiometry (GEP) and UV-Vis spectroscopy at 25.0 °C and I=0.1 mol⋅dm−3 KNO3 ionic strength. For the Ni–(L) x –(OH) y and Co–(L) x –(OH) y systems, with L = TAPSO or DIPSO, the proposed final models and overall stability constants were obtained by combining results from both techniques. For the Ni–(L) x –(OH) y systems, the measured values of the stability constants are log 10 β NiL=3.0±0.1 and log 10 β NiL2=4.8±0.1 for L = TAPSO, and log 10 β NiL=2.7±0.1 and log 10 β NiL2=4.6±0.1 for L = DIPSO. For the Co–(L) x –(OH) y systems, the overall stability constants are log 10 β CoL=2.2±0.1, log 10 β CoL2=3.6±0.2 and log 10 β CoL(OH)=7.6±0.1 for L = TAPSO, and log 10 β CoL=2.0±0.1 and log 10 β CoL(OH)=7.8±0.1 for L = DIPSO. For both buffers, the CoL(OH) species is characterized by a major structural rearrangement.

Thermodynamic studies of actinide complexes. 1. A reappraisal of the solution equilibria between plutonium(IV) and ethylenediaminetetraacetic acid (EDTAH4) in nitric media

Abstract A detailed reevaluation of the complexation equilibria of plutonium(IV) with the polyaminocarboxylic sequestering agent EDTA4− has been performed in 1 M (H,K)NO3 media at 298 K by means of visible absorption spectrophotometry and glass-electrode potentiometry at millimolar concentration levels. The high binding affinity even under strongly acidic conditions supports the exclusive formation of the neutral Pu(EDTA) complex over the range 0.01 ≤ [H+] ≤ 0.9 M with an apparent formation constant of log β110 = 25.8(1) at 0.9 M HNO3. Extrapolation to zero ionic strength using the SIT approach provides the first ever-reported NEA–TDB compliant estimate of β 110 0 ( log β 110 0 = 32.2 ( 3 ) ) . A global modeling procedure of the potentiometric data collected for three different metal over ligand ratios (1:1, 1:1.5, and 1:2) ascertained the formation of four additional species for pH values comprised between 2 and 6.5, namely [Pu(EDTA)(OH)]−, [Pu(EDTA)2H2]2−, [Pu(EDTA)2H]3−, and [Pu(EDTA)2]4−. The visible absorption spectra for the first three complexes have also been determined. Data recorded above pH 3.5 (for a 1:1 molar ratio) or 6.5 (for a 1:2 molar ratio) were finally excluded from the global fitting procedure as speciation calculations suggested the precipitation of amorphous Pu(OH)4(am) according to the latest critical value quoted in the literature for its solubility product.

Metal-Ion Selectivity Produced by C-Alkyl Substituents on the Bridges of Chelating Ligands: The Importance of Short H−H Nonbonded van der Waals Contacts in Controlling Metal-Ion Selectivity. A Thermodynamic, Molecular Mechanics, and Crystallographic Study

The effect on metal-ion selectivity of the use of cyclohexenyl bridges in ligands in place of ethylene bridges is examined (selectivity is defined as the difference in log K1 for one metal ion relative to that of another with the same ligand). The syntheses of N,N'-bis(2-hydroxycyclohexyl)ethane-1,2-diamine (Cy2-en), N,N'-bis(2-hydroxycyclohexyl)propane-1,3-diamine (Cy2-tn), and 1,7-bis(2-hydroxycyclohexyl)-1,4,7-triazaheptane (Cy2-dien) are reported. The crystal structures of [Cu(Cy2-tn)(H2O)](ClO4)2 (1) and [Cu(Cy2-dien)](ClO4)2 (2) are reported. Characteristics of 1: monoclinic, Pn space group, a=11.627(2) A, b=7.8950(10) A, c=12.737(8) A, beta=98.15(3) degrees, Z=2, R=0.0524. Characteristics of 2: orthorhombic, Pbca space group, a=21.815(16) A, b=8.525(7) A, c=25.404(14) A, Z=8, R=0.0821. Structure 1 has the Cu(II) atom coordinated in the plane of the ligand to the two N donors and two O donors, with a long bond to an axially coordinated water molecule. 2 has three N donors, and one hydroxyl O donor from the ligand is coordinated in the plane around the Cu(II) atom, with the second hydroxyl O donor of the ligand occupying an axial site with a long Cu-O bond. The salient feature of both structures is the short H-H nonbonded distance between H atoms on the cyclohexenyl bridges and H atoms on the ethylene bridges of the ligand. These short contacts are important in explaining the metal-ion selectivities of these ligands. Formation constants, determined by glass-electrode potentiometry, for the Cy2-en (Cu(II), Ni(II), Zn(II), Cd(II), Pb(II)), Cy2-dien (Cu(II), Zn(II), Cd(II), Pb(II)), and Cy2-tn (Cu(II), Zn(II), Cd(II)) complexes are reported. These all show a strong shift in selectivity toward smaller metal ions compared with the analogous ligands, where ethylene bridges are present in place of the cyclohexenyl bridges of the ligands studied here. Molecular mechanics (MM) calculations are used to analyze these changes in selectivity. These calculations show that the short H-H contacts become shorter with increasing metal-ion size, which is suggested as the cause of the shift in the selectivity of ligands in favor of smaller metal ions when ethylene bridges are replaced with cyclohexenyl bridges. MM calculations are also used to rationalize, in terms of short H-H contacts, the fact that when the chelate ring contains two neutral O donors, more stable complexes result with cis placement of the donor atoms on the cyclohexenyl bridge, but with two N donors, trans placement of the donor atoms results in more stable complexes.

Dioxouranium(VI)-Carboxylate Complexes. Interaction of UO 2 2+ with 1,2,3,4,5,6-Benzenehexacarboxylate (Mellitate) in 0≤I(NaClaq)≤1.0 mol⋅L−1

The formation constants of dioxouranium(VI)—1,2,3,4,5,6-benzenehexacarboxy- late [mellitate(6−)] complexes were determined in NaCl aqueous solutions at 0.1 ≤ I ≤ 1.0 mol·L−1 and t = 25 ∘C by ISE-[H+] glass-electrode potentiometry. The speciation model obtained at each ionic strength includes the following species: ML4−, MLH3−, MLH22 −, MLH3−, M2L2−, MLOH5− and ML(OH)26− (M = UO22 + and L6− = mellitate). The ionic strength dependence of the protonation constants of mellitate and of the metal-ligand complexes was investigated using the SIT (Specific Ion Interaction Theory) approach. Formation constants at infinite dilution are [for the generic equilibrium \(p{\rm UO}_{\rm 2}^{{\rm 2 + }} + q({\rm L}^{{\rm 6} - }) + r{\rm H}^{\rm + }\rightleftharpoons({\rm UO}_{\rm 2}^{{\rm 2 +}})_p({\rm L})_q {\rm H}_r^{(2p - 6q + r)};\,\beta _{pqr}\)]: log10β110 = 10.155, log10β111 = 16.084, log10β112 = 20.749, log10β113 = 24.038, log10β210 = 17.936, log10β11−1 = 2.327 and log10β11−2 = −6.804. Simple linear relationships between the formation constants and the stoichiometric coefficients of reactants are reported. The sequestering capacity of mellitate towards UO22+ was quantified using a sigmoid Boltzman-type equation.

Influence of electronic and steric effects on stability constants and electrochemical reversibility of divalent ion complexes with glycine and sarcosine: A glass electrode potentiometric, sampled direct current polarographic, virtual potentiometric, and molecular modelling study

Cd II complexes with glycine (gly) and sarcosine (sar) were studied by glass electrode potentiometry, direct current polarography, virtual potentiometry, and molecular modelling. The electrochemically reversible Cd II–glycine–OH labile system was best described by a model consisting of M(HL), ML, ML 2, ML 3, ML(OH) and ML 2(OH) (M = Cd II, L = gly) with the overall stability constants, as log β, determined to be 10.30 ± 0.05, 4.21 ± 0.03, 7.30 ± 0.05, 9.84 ± 0.04, 8.9 ± 0.1, and 10.75 ± 0.10, respectively. In case of the electrochemically quasi-reversible Cd II–sarcosine–OH labile system, only ML, ML 2 and ML 3 (M = Cd II, L = sar) were found and their stability constants, as log β, were determined to be 3.80 ± 0.03, 6.91 ± 0.07, and 8.9 ± 0.4, respectively. Stability constants for the ML complexes, the prime focus of this work, were thus established with an uncertainty smaller than 0.05 log units. The observed departure from electrochemical reversibility for the Cd–sarcosine–OH system was attributed mainly to the decrease in the transfer coefficient α. The MM2 force field, supplemented by additional parameters, reproduced the reported crystal structures of diaqua-bis(glycinato-O,N)nickel(II) and fac-tri(glycinato)-nickelate(II) very well. These parameters were used to predict structures of all possible isomers of (i) [Ni(H 2O) 4(gly)] + and [Ni(H 2O) 4(sar)] +; and (ii) [Ni(H 2O) 3(IDA)] and [Ni(H 2O) 3(MIDA)] (IDA = iminodiacetic acid, MIDA = N-methyl iminodiacetic acid) by molecular mechanics/simulated annealing methods. The change in strain energy, Δ U str, that accompanies the substitution of one ligand by another (ML + L′ → ML′ + L), was computed and a strain energy Δ U str = +0.28 kcal mol −1 for the reaction [Ni(H 2O) 4(gly)] + + sar → [Ni(H 2O) 4(sar)] + + gly was found. This predicts the monoglycine complex to be marginally more stable. By contrast, for the reaction [Ni(H 2O) 3IDA] + MIDA → [Ni(H 2O) 3MIDA] + IDA, Δ U str = −0.64 kcal mol −1, and the monoMIDA complex is predicted to be more stable. This correlates well with (i) stability constants for Cd–gly and Cd–sar reported here; and (ii) known stability constants of ML complex for glycine, sarcosine, IDA, and MIDA.

Stereoselective synthesis of cobalt(III) anionic complexes with chiral pyruvylaminoacid oximes and metal–ligand interactions in aqueous solution

A series of cobalt(III) anionic complexes with hydroxyimino analogs of dipeptides – oximes of pyruvylglycine, pyruvyl-l-alanine, pyruvyl-l-methionine and pyruvyl-l-phenylalanine (H2pamaco, amac=amino acid) of composition Cat3[Co(H−1pamaco)2]·nH2O (Cat – a monovalent metal cation) has been synthesized and investigated by UV–Vis, CD and 1H NMR spectroscopy. It was established that for the two latter ligands, non-racemic mixtures of two diastereomeric complexes were formed as a result of synthesis. In comparison with the complex containing pyruvyl-l-alanine, in which the relative content of R (C2) and S (C2) isomers is approximately equal, the presence of bulky substituents in the molecules of Met- and Phe-containing ligands results in a significant discrimination in formation of the S (C2) isomer. This conclusion was drawn upon analysis of the CD and NMR spectral data as well as from molecular modeling. The relative content of the diastereomers was evaluated on the basis of NMR data. The protonation constants of the ligands have been determined in aqueous solution by glass electrode potentiometry, whereas their interactions with Co(II) were studied both under argon and oxygen atmosphere.

Chemical speciation of copper(ii) diaminediamide derivative of pentacycloundecane—a potential anti-inflammatory agent

Formation constants of copper(ii), zinc(ii) and calcium(ii) with 3,5-diaminodiamido-4-oxahexacyclododecane (cageL) has been studied by glass electrode potentiometry at 25 degrees C and an ionic strength of 0.15 mol dm(-3). Copper(ii) forms more stable complexes with cageL than zinc(ii) and calcium(ii). Metal ion complexation promotes deprotonation and coordination of the amide nitrogens resulting in overall tetragonal coordination of Cu(2+) suggested by the UV-visible electronic spectra. Speciation calculations using a blood plasma model suggest that zinc(ii) and calcium(ii) are good competitors of copper(ii) in vivo. Bio-distribution experiments using (64)Cu-labelled Cu(ii)-cageL show that about 50% dose of the complex is retained in the body after 24 h.

Thermodynamic and spectroscopic study of the interaction of Cu(II), Ni(II), Zn(II) and Ca(II) ions with 2-amino-N-(2-oxo-2-(2-(pyridin-2-yl)ethyl amino)ethyl)acetamide, a pseudo-mimic of human serum albumin

The protonation equilibria of 2-amino-N-(2-oxo-2-(2-(pyridin-2-yl)ethyl amino)ethyl)acetamide ([H2(556)–N]) and the complexation of this ligand with Cu(II) Ca(II), Zn(II) and Ni(II) have been studied by glass electrode potentiometry and UV–visible spectrophotometry. From pH ∼2.00–11.00, five models for Cu(II) with the following complexes; MLH, ML, MLH−1, MLH−2 and MLH−3 were generated and observed to describe the experimental data equally well as far as the statistical criteria were concerned. The MLH−2 complex predominates at physiological pH in all five models, while the MLH−1 complex species exists only at low concentration in two models. The coordination in the MLH−2 complex suggested the involvement of one amino, two deprotonated peptides and one pyridyl nitrogen atoms. Molecular mechanics (MM) calculations confirmed the MLH−2 complex as the most stable species. Speciation calculations, using a blood plasma model, predicted that the Cu(II)–[H2(556)–N] complex is able to mobilize Cu(II). Octanol/water partition of CuLH−2 showed that 30% of the complex went into the octanol phase, hence promoting percutaneous absorption of copper. The complex is a poor mimic of native copper–zinc superoxide dismutase.

Copper(II) interaction with 3,5-diisopropylsalicylic acid (Dips): New insights on its role as a potential [rad]OH inactivating ligand

The purpose of this study was to identify the low molecular mass complexes formed between copper(II) and 3,5-diisopropylsalycilic acid (Dips) in physiological conditions. Copper(II)–Dips complex equilibria were determined using glass electrode potentiometry and their solution structures checked by UV–visible (UV–vis) spectrophotometry. Because of the low solubility of Dips in water, the equilibria were investigated in different water/ethanol mixtures. Formation constants were extrapolated to 100% water and then compared with the values obtained for the other anti-inflammatory drugs previously studied. Given the prime role of histidine as the copper(II) ligand in blood plasma, copper(II)–histidine–Dips ternary equilibria were studied under similar experimental conditions. Computer simulations of copper(II) distribution relative to different biofluids, gastrointestinal (g.i.) fluid and blood plasma, show that like salicylic and anthranilic acids, Dips favors g.i. copper absorption, but cannot exert any significant influence on plasma copper distribution. Moreover, Dips can mobilize increasing fractions of copper(II) as the pH decreases. In conclusion, Dips seems to correspond to the notion of OH-inactivating ligand (OIL) as determined for anthranilic acid.

Modelling of Pb–(TAPS) x–(OH) y system and refinement of stability constants in the region of lead hydrolysis and lead hydroxide precipitation

The influence of [(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS) on solutions containing lead(II) was studied by direct current polarography (DCP) and glass electrode potentiometry (GEP). The readings were taken at fixed total TAPS to total lead(II) concentration ratios and various pH values, at 25.0 ± 0.1 °C and ionic strength 0.1 M KNO 3. Due to the basic p K a of the ligand, which occurs in the pH range where large amount of lead polynuclear species are formed, and the occurrence of ligand adsorption, that disabled the use of high concentrations of TAPS on DCP experiments, GEP and DCP experimental conditions were put to the limit in order to provide the correct Pb–TAPS–OH model and reliable stability constants. The proposed final model is: PbL, PbL 2, PbL 2(OH) and PbL 2(OH) 2 with overall stability constants values, as log β, 3.27 ± 0.06, 6.5 ± 0.1, 12.7 ± 0.1 and 17.27 ± 0.06, respectively. A comparative analysis of the strength of complexation of TAPS and a structural related buffer, 2-hydroxy-3-[tris(hydroxymethyl)methylamino]-1-propanesulfonic acid (TAPSO), with lead is also discussed.

Copper chelating anti-inflammatory agents; N1-(2-aminoethyl)- N2-(pyridin-2-ylmethyl)-ethane-1,2-diamine and N-(2-(2-aminoethylamino)ethyl)picolinamide: An in vitro and in vivo study

An in vitro and in vivo study of some copper chelating anti-inflammatory agents for alleviation of inflammation associated with rheumatoid arthritis (RA) has been conducted. Two copper chelating agents, N 1-(2-aminoethyl)- N 2-(pyridin-2-ylmethyl)ethane-1,2-diamine ([555-N]) and N-(2-(2-aminoethylamino)ethyl)picolinamide ([H(555)-N]) have been synthesized as their hydrochloride salt; their protonation constants and formation constants with Cu(II), Zn(II) and Ca(II) determined by glass electrode potentiometry at 298 K and an ionic strength of 0.15 M. Cu(II) formed stable complexes at physiological pH while the in vivo competitors, Zn(II) and Ca(II) formed weak complexes with both chelating agents. Both [555-N] and [H(555)-N] showed better selectivity for Cu(II) than for Zn(II) and Ca(II). Electronic spectra for species formed at physiological pH suggest a square planar geometry. Speciation calculations using a blood plasma model predicted that these copper chelating agents are able to mobilize Cu(II) in vivo, while bio-distribution studies of their 64Cu(II)-labelled complexes at physiological pH showed tissue accumulation and retention indicating an encouraging biological half life.

Challenges in modelling and optimisation of stability constants in the study of Cu–(TAPS) x–(OH) y system by polarography

This work describes the application of polarography, a technique scarcely used for modelling and optimisation of stability constants, in the study of copper complexes with [(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS). Direct current polarography (DCP), using low total copper ion and large total ligand to total copper concentration, enabled the full characterization of Cu–(TAPS) x –(OH) y system, whose complexation occurs in the pH range of copper hydrolysis and Cu(OH) 2 precipitation. Cu–(TAPS) x –(OH) y system was studied by DCP and glass electrode potentiometry (GEP) in aqueous solution at fixed total ligand to total metal concentrations ratios and varied pH values (25.0 °C; I = 0.1 M, KNO 3). The predicted model, as well as the overall stability constants values, are (as log β): CuL + = 4.2, CuL 2 = 7.8, CuL 2(OH) − = 13.9 and CuL 2(OH) 2 2− = 18.94. GEP only allowed confirming the stability constants for CuL + and CuL 2 and was used to determine the p K a of TAPS, 8.342. Finally, a briefly comparative analysis between TAPS and other structural related buffers was done. Evaluation based on log β CuL versus p K a revealed that TES, TRIS, TAPS and AMPSO coordinated via amino and hydroxymethylgroups forming a five-membered chelate ring. For BIS-TRIS and TAPSO, and possibly DIPSO, one or more five-membered chelate rings involving additional hydroxyl groups are also likely formed.