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[Display omitted] • The acid–base properties of pregabalin were investigated under different conditions. • The findings indicate that at the pH of seawater (pH = 8.2), approximately 58 % of PGB is complexed with Cu2+ and ∼41 % exists as LH0 species. • For the Zn2+/PGB system, only the ∼28 % of PGB is complexed and ∼70 % of PGB exists as protonated species. The thermodynamics of the interaction between (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) and protons was studied potentiometrically at different temperatures (288.15 ≤ T /K ≤ 310.15), ionic strengths (0.16 ≤ I /mol kg−1(H 2 O) ≤ 0.97, NaCl), (0.11 ≤ I /mol kg−1(H 2 O) ≤ 1.11, (C 2 H 5) 4 NI), (0.10 ≤ I /mol kg−1(H 2 O) ≤ 1.03, NaClO 4 , only at T = 298.15 K). The protonation constants at infinite dilution and the corresponding enthalpy change values were determined, as well as their parameters for the dependence on the temperature and ionic strength. The results showed that the protonation reactions are exothermic, and that the entropic contribution is the driving force of the processes. Formation constants of pregabalin (L) with Zn2+, Cu2+, Ca2+, and Mg2+ were determined in NaCl(aq) at different ionic strength values, at 298.15 K. Different speciation models were proposed for the various metal/Pregabalin systems: ZnHL2+, ZnLOH0 (aq) , CuL+, CuL 2 0 (aq) , CaL+, CaHL2+, and MgL+, depending on the different acid–base properties of the metals and the possible formation of sparingly soluble species. The modelling of the thermodynamic formation parameters respect to the temperature and ionic strength variation was carried out by using both the Specific Ion Interaction Theory (SIT) and an extended Debye-Hückel type equation. Being Pregabalin an emerging contaminant, it was interesting to investigate its distribution in presence of the investigated metal cations in aqueous solution simulating both biological fluid (urine) and natural water (seawater). [ABSTRACT FROM AUTHOR]

[Display omitted] • The ionic strength and temperature dependence of the equilibrium constants were modeled using Specific Ion Interaction theory (SIT) and a modified Debye-Hückel equation containing a Van't Hoff term. • Sequestering ability of alendronate toward Mg2+ and Ca2+ has been evaluated by means of the pL 0.5 parameter. • Simulation of the Mg2+ and Ca2+/alendronate species in human blood plasma. The thermodynamics of interaction of a second-generation bisphosphonate drug, 4-amino-1-hydroxy-1-phosphonobutyl phosphonic acid mono sodium (sodium alendronate) with H+, Ca2+ and Mg2+ has been investigated. The protonation constants were determined in NaCl and (C 2 H 5) 4 NI aqueous solutions at different ionic strengths (0.10 ≤ I /mol kg−1(H 2 O) ≤ 1.02) and temperatures (288.15 ≤ T /K ≤ 310.15) by using the ISE-[H+] potentiometry. The differences of the log K i H in the two ionic media were interpreted in terms of activity coefficient variations and formation of Na+ weak complexes. The interactions with Mg2+ and Ca2+ were studied in NaCl (aq) (0.10 ≤ I / mol kg−1 (H 2 O) ≤ 1.02) and T = 298.15 K. Two different speciation models were obtained; Ca2+: CaH 2 L, CaHL, CaL. Mg2+: MgH 3 L, MgH 2 L, MgHL, MgL. The dependence of the thermodynamic parameters on the ionic strength and temperature was modelled by means of the Specific Ion Interaction Theory (SIT) and a modified Debye-Hückel equation including a term for the dependence on T /K. The first two protonation equilibria are exothermic, and the reactions are not favoured by an increase of the temperature whilst the last two are endothermic. The entropic contribution resulted to be the driving force of the reactions. The sequestering ability of alendronate towards the two metal cations was quantified by means of the pL 0.5 parameter calculated at different pHs and ionic strengths. It resulted that alendronate has a higher sequestration toward Mg2+ with respect to Ca2+. A simulation of the alendronate behaviour in human blood plasma was carried out. [ABSTRACT FROM AUTHOR]

Deferiprone, generally, is considered an important chelating agent for Fe3+ overload. From a literature data analysis, a lack of information on the interaction of this molecule toward a series of metal cations emerged, inducing to fill out the topic. The complexing ability of deferiprone toward Ca2+, Mg2+, Cd2+ and Pb2+ was studied by potentiometry and 1H NMR spectroscopy, in KCl aqueous solutions at different ionic strength values (0.1 ≤ I /mol dm−3 ≤ 1.0) and T = 298.15 K. The same speciation model featured by the ML, ML 2 , ML 3 and ML(OH) (M = metal and L = deferiprone or DFP) species was obtained for Cd2+ and Pb2+; the formation constants calculated at infinite dilution are: logT β = 7.23±0.02, 12.47±0.03, 16.70±0.04, and −2.53±0.04, respectively for Cd2+ and 9.91±0.01, 15.99±0.02, 19.93±0.05 and 0.99±0.02 for Pb2+. Only two species, namely ML and ML 2 , were determined for Ca2+ and Mg2+, whose formation constants at infinite dilution are respectively: 3.72±0.01 and 6.50±0.02, for the first one, 5.31±0.01 and 9.58±0.01, for the second. The ligand sequestering ability and affinity toward M2+ were evaluated by determining the pL 0.5 and pM parameters at different pHs and ionic strengths. The results suggest that deferiprone has the best complexing and sequestering ability toward Pb2+, followed by Cd2+, Mg2+ and Ca2+, respectively. 1H NMR studies confirmed the DFP affinity for Cd2+ and Pb2+, and in combination with DFT calculations showed that metal cations are bound to the hydroxo-oxo moiety of the pyridinone ring. The data reported in this study provide information on the possible employment of a small molecule like deferiprone, as a chelating and sequestering agent for Pb2+ accumulation or overload from environmental and biological matrices. [Display omitted] • Speciation study on the deferiprone interactions toward Ca2+, Mg2+, Cd2+, Pb2+. • Potential use of deferiprone ligand to remove Pb2+ contamination. • Future applications on real environmental matrixes. [ABSTRACT FROM AUTHOR]

Protonation of nicotinic acid has been investigated by means of potentiometric titrations at different temperatures 283.15 ≤ T (K) ≤ 383.15 and ionic strengths of NaCl(aq), 0.12 ≤ I (mol·kg−1) ≤ 4.84 and mixed NaCl with MgCl2 or CaCl2. Stability constants of the CaL+ and MgL+ species were obtained by means of the ΔpK method. Different models (e.g. Debye–Hückel type equation, Specific Ion Interaction Theory, Pitzer and van't Hoff) were applied to account for the ionic strength and temperature dependences, in order to obtain data in a standard state and parameters to calculate stability constants in any point of our experimental domain. Speciation studies were performed simulating the conditions of natural fluids. Literature data were investigated for comparison with the experimental results here obtained. [ABSTRACT FROM AUTHOR]

This paper reports the results of a study on the determination of the protonation constants of MoO 4 2 − , in NaCl aq , NaNO 3aq , KCl aq , at different ionic strengths (0 < I /mol dm − 3 ≤ 5.0 in NaCl aq, 0 < I /mol dm − 3 ≤ 3.0 in NaNO 3aq and KCl aq ) and temperatures (278.15 ≤ T /K ≤ 318.15 in NaCl aq , only 298.15 K in NaNO 3aq and KCl aq ), by potentiometric (ISE-H + glass electrode) and spectrophotometric (UV/Vis) titrations. After a critical analysis of results and literature findings, the proposed speciation model takes into account the formation of two monomeric and four heptameric species, namely: MoO 4 H − , MoO 4 H 2 , (MoO 4 ) 7 H 8 6 − , (MoO 4 ) 7 H 9 5 − , (MoO 4 ) 7 H 10 4 − and (MoO 4 ) 7 H 11 3 − . Due to the complexity of the system, and to discrepancies of literature findings, particular attention has been paid to the determination of the stability of monomeric species, by performing measurements at very low concentrations, in which the polymerization processes do not occur. Data obtained have then been used to model the dependence of the acid-base properties of molybdate on medium, ionic strength and temperature by models commonly used for these purposes, namely the Extended Debye-Hückel (EDH), the classical Specific ion Interaction Theory (SIT), Pitzer equations, and van't Hoff (for the dependence on temperature). These last results, some of them obtained for the first time in this work, can be exploited for the modeling of the speciation of MoO 4 2 − in a wide range of conditions typical of natural waters and biological fluids, as well as in many aqueous systems of technological/industrial importance, where molybdate can play key roles. [ABSTRACT FROM AUTHOR]

This paper reports the results of an investigation carried out on the interaction between Zn(II) and some hydroxocarboxylic ligands (L), namely: malate (Mala), tartrate (Tar) and citrate (Cit). The stability constants of the mono- and polynuclear ZnHL species were determined by potentiometric measurements at T = 298.15 K in different ionic media, NaCl and NaNO, at different ionic strengths: I = 0.15 mol dm (NaCl) and 1.00 mol dm (NaCl and NaNO). As a further contribution to the study of the formation of mixed species, that are of particular importance in fluids that hyperaccumulated metal ions, the ternary interactions between two different metals and a ligand (Zn/Sn/hydroxocarboxylic ligands) were also investigated. The formation of the hetero-metal complexes produces an enhancement of the stability of the complexes with respect to the same homo-metal ones, shifting significantly the pH of precipitation of the sparingly soluble species and increasing the mobility and bioavailability of the species. From the analysis of experimental data at I = 1.00 mol dm in NaCl and NaNO, it results that the stability constants in NaCl are significantly higher than the ones in NaNO. The higher stability of the species in NaCl can be explained in terms of ion pairs formation with chloride ion. As an example, for the hetero-metals/Mala /chloride system, the following stability constants, on the basis of the general reaction: mixed-complex + Cl = mixed-complex/Cl (quaternary species), we obtained: log K = 0.48, log K = 0.36, log K = 0.82 for ZnSnMalaCl, ZnSn(Mala)Cl, and ZnSn(Mala)OHCl, respectively. The sequestering ability of the three ligands toward Zn was evaluated, at different experimental conditions, by means of the empirical parameter, pL. The effect of the chloride anion on the stability of various species and on the sequestration of the metal was also evaluated. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: The interactions between some xanthine derivatives: caffeine (Cf), theophylline (Tp), theobromine (Tb), and histamine (Hm) with phytate (Phy) were studied at T =298.15K and I =0.5molL−1 in aqueous NaCl solution using ISE-[H+] potentiometry. For all of the investigated systems, [(Phy)(L)H q ](q −7) species (q =4 to 9, depending on the maximum protonation degree of the ligand) were formed in high yields (30–90%). The stability constants of the systems varied; higher stability was observed for the [(Phy)(Tb)H q ](q −7) (5≤ q ≤8) species. For the [(Phy)(Tb)H8]+ and [(Phy)(Tb)H7] species, we obtained values of log K 8 =8.1 and log K 7 =5.58, respectively. The formation ΔH and TΔS parameters were determined for the Phy–Cf system at I =0.5molL−1 in NaCl(aq) by calorimetric titrations. As an example, for the [(Phy)(Cf)H5]2− species, we obtained the following values: ΔH =−4.0±0.2kJmol−1, −ΔG =14.6±0.5kJmol−1 and TΔS =10.5±0.8kJmol−1. [Copyright &y& Elsevier]

Abstract: The interaction between protonated branched poly(ethylenimine) [BPEI] and phytate (1,2,3,4,5,6 hexakis (di-hydrogen phosphate) myo-inositol) [Phy] was studied potentiometrically. The measurements were carried out at t =25 °C and at low ionic strength values, without addition of supporting electrolyte, to avoid interferences with other anions and cations. In order to simplify the data treatment, BPEI was considered as a simple tetramine. Different species Phy(BPEI)H j , with j =6,7,8, and Phy(BPEI)2H7 were found, having quite high stability. The ability of phytate to sequester BPEI was quantified by considering the parameter pL50, namely the concentration (−log [Phy]tot) necessary to bind 50% of polyammonium cation (as trace). In our experimental conditions, for the system phytate–BPEI-proton we have pL50 =7.01, at pH=7.4 and I =0.04 mol L−1. As for other phytate–polyammonium cation systems, the stability of the phytate–BPEI species is strictly proportional to the charges involved in the formation reactions. Therefore, it was possible to calculate the free energy contribution per bond, ΔG b U =4.4±0.4 kJ mol−1. The dependence on temperature and ionic strength of the stability of phytate-low/high molecular weight polyammonium cations species, was studied using some semiempirical equations and enthalpy data for the protonation of both components. The dependence on temperature of the stability is quite low and the variation of pL50 in the range 15≤ t/°C≤37 is less than 0.5 log units. On the contrary, the effect of ionic strength is highly significant, with a lowering of pL50 of ≈2 log units (I =0 to 0.15 mol L−1). [Copyright &y& Elsevier]

The sequestering capacity of synthetic and naturally occurring polycarboxylate ligands towards monomethylmercury( II) was evaluated by stability quantitative data on the interaction of CH3Hg+ with different molecular weight synthetic polyacrylates (2 and 20 kDa average M.wt) and alginate (70-100 kDa) extracted from brown algae Macrocystis pyrifera. The influence of ionic medium was evaluated by measurements on the CH3Hg+-polyacrylate systems in NaNO3 medium at different ionic strengths (0.10, 0.25, 0.50 and 0.75 mol -1), and a Debye-Hückel type equation was used for the dependence of complex formation constants on ionic strength. Measurements on the CH3Hg+-alginate system were carried out at l=0.10 mol L-1 in NaNO3 medium. By using the stability data, the sequestering capacity of both ligands towards monomethylmercury(II) was determined at different pH values. Results obtained show that the binding ability of polyacrylic ligands (PAA) is stronger than the alginate (AA), following the trend PAA (20 kDa) > PAA (2 kDa) > AA. [ABSTRACT FROM AUTHOR]

Abstract: In the present paper, some results of an investigation (at t =25°C by potentiometry, ISE-H+ glass electrode) on the sequestering ability of five different polyaminopolycarboxylic ligands [Nitrilotriacetate (NTA), ethylenediamine-N,N,N′,N′-tetraacetate (EDTA), ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetate (EGTA), diethylenetriamine-N,N,N′,N″,N″-pentaacetate (DTPA), triethylenetetraamine-N,N,N′,N″,N′′′,N′′′-hexaacetate (TTHA)] towards dioxouranium(VI) cation in sodium chloride aqueous solutions, at I =0.7molL−1 are reported. Calculations performed on potentiometric data gave evidence of the formation of the following species (log β in parenthesis): UO2(NTA)H0 (12.27); UO2(NTA)− (8.21); UO2(NTA)OH2− (2.39); UO2(EDTA)H− (15.19); UO2(EDTA)2− (9.81); UO2(EDTA)OH3− (3.58); UO2(EGTA)H− (17.35); UO2(EGTA)2− (11.60); UO2(EGTA)OH3− (2.77); UO2(DTPA)H2 − (22.14); UO2(DTPA)H2− (17.86); UO2(DTPA)3− (11.79); UO2(DTPA)OH4− (3.09); UO2(TTHA)H3 − (28.41); UO2(TTHA)H2 2− (24.73); UO2(TTHA)H3− (19.14); UO2(TTHA)4− (12.12). In presence of complexones, the formation of scarcely soluble species occurs at higher pH values than in simple UO2 2+ aqueous solutions. The stability of dioxouranium(VI)–polyaminopolycarboxylate species follows the trend: TTHA>DTPA>EGTA>EDTA>NTA, it is dependent on the ligand structure and this dependence was modeled. Polyaminopolycarboxylate ligands are good sequestering agents towards UO2 2+, indicating the possibility of being employed in the UO2 2+ polluted sites remediation, and in the chelating therapy in medicine. A literature data critical evaluation was made, evidencing the high discrepancies occurring between different authors in both the stability constant values and the proposed speciation models. [Copyright &y& Elsevier]

Abstract: Interaction of dioxouranium(VI) (uranyl) ion with ATP was studied by ligand/proton and metal/hydroxide displacement technique, at very low ionic strength and at I =0.15 mol L− 1, in aqueous Me4NCl and NaCl solutions, at t =25 °C. Measurements were carried out in the pH range 3–8.5, before the formation of precipitate. Computer analysis allowed us to find the quite stable species UO2(ATP)H2 0, UO2(ATP)H−, UO2(ATP)2−, UO2(ATP)2 6−, UO2(ATP)2H2 4− and UO2(ATP)(OH)3− whose formation constants are (at I =0 mol L− 1) logβ 112 =18.21, logβ 111 =14.70, logβ 110 =9.14, logβ 120 =12.84, logβ 122 =24.82, and logβ 11-1 =2.09, respectively. Different values were obtained in the above ionic media at I =0.15 mol L− 1 and the dependence on the ionic medium was interpreted in terms of interactions between the negatively charged complex species and cations of supporting electrolytes. The species more stable in NaCl than in Me4NCl are those with the highest negative charge, UO2(ATP)2 6− and UO2(ATP)2H2 4−, and the extra stability of these species can be attributed to the interaction with Na+. Speciation profiles show that ATP can suppress UO2 2+ hydrolysis, and that in the neutral to slightly alkaline range the yield of complex UO2–ATP species is quite high. Comparison with other metal–ATP systems is also given in order to recognize the possibility of binding competition of uranyl ion in metal–ATP requiring enzymes for biochemical processes. [Copyright &y& Elsevier]

Abstract The binding ability of diethylene triamine penta-acetate (dtpa5 ) and triethylene tetraamine hexaacetate (ttha6 ) ligands towards major components, 11+, Na+, Mg2+ and Ca2+, of natural waters was studied in both single and mixed ionic media at different ionic strengths and at `I'=25 °C. Some measurements, performed in Mg2+-Ca2+ mixtures, allowed us to find the formation of new mixed species MgCa(dtpa), MgCa(ttha) and MgCaH(ttha), here reported for the first time. All the complexes formed in the various systems were characterized in terms of both stoichiometry and stability, and an attempt was made to find general rules for the stability of mixed metal com- plexes in comparison with that of simple species. To obtain quantitative information on the complexing ability of dtpa and ttha in seawater, measurements have been car- ried out in artificial seawater ionic medium (Na+, K+, Ca2+, Mg2+, Cl and SO42 ). Calculations, performed by considering the salt mixture as single salt BA, allowed us to find some quite stable BiHjL species. Under the natural seawater conditions [S(salinity)=35], we found for the most important species logβ B(dtpa)=9.64 and log βB2(dtpa)= 10.2. Literature data comparison is also reported. [ABSTRACT FROM AUTHOR]

Acid–base properties of two sodium polymethacrylates (W=4000 and 5400 Da) were studied potentiometrically in aqueous solution at 25 °C. Measurements were made in different salt solutions: LiCl 0.1–1.5, NaCl 0.1–2, KCl 0.1–2, Et4NI 0.1–0.75 mol l−1, and in artificial seawater in the salinity range 10≤S≤45. Protonation data were analysed by two different models and the dependence of the relative parameters on ionic strength were calculated. Measurements performed in interacting media (alkali metal chlorides and artificial seawater) were interpreted in terms of complex formation, and the relative formation parameters are reported. Previous data on the interaction of a higher molecular weight (W=230 000 Da) polymethacrylic acid with alkaline metal cations and Ca2+ were reanalysed in the light of correct procedure which takes the effective polyanion charge into account. The speciation of methacrylates, in aqueous solutions containing the major constituents of natural fluids, is discussed in relation to the various parameters that influence the stability of different species formed. [Copyright &y& Elsevier]

The interaction of adenosine-, uridine-, inosine- and guanosine-5′-monophosphates with protonated ethylenediamine, putrescine, cadaverine, spermidine and spermine, was studied potentiometrically, at t=25°C. The species ALH20 are formed with diamines, ALH20, ALH3+ with triamine, and, ALH20, ALH3+ and ALH42+ with tetramine. The stability of these species is strongly dependent on the product charge, ζ=∣zanionzcation∣: the ratio logKr/ζ is fairly constant, and, for the different systems, varies from 0.53 to 0.59. This behaviour is very similar to that shown by the analogous species of ATP (logKr/ζ=0.52), already studied in these laboratories. Two other factors are taken into account for the analysis of stability data, i.e., the length of alkyl chain(s) in the amine, and the difference between total and protonated amino groups. These factors are related to steric arrangement and to the possibility of hydrogen bonding contribution. The relevance of these complexes in the chemical speciation of biological fluids is discussed. [ABSTRACT FROM AUTHOR]

The acid–base properties of two bifunctional 3-hydroxy-4-pyridinone ligands and their chelating capacity towards Zn2+, an essential bio-metal cation, were investigated in NaCl aqueous solutions by potentiometric, UV-Vis spectrophotometric, and 1H NMR spectroscopic titrations, carried out at 0.15 ≤ I/mol −1 ≤ 1.00 and 288.15 ≤ T/K ≤ 310.15. A study at I = 0.15 mol L−1 and T = 298.15 K was also performed for other three Zn2+/Lz− systems, with ligands belonging to the same family of compounds. The processing of experimental data allowed the determination of protonation and stability constants, which showed accordance with the data obtained from the different analytical techniques used, and with those reported in the literature for the same class of compounds. ESI-MS spectrometric measurements provided support for the formation of the different Zn2+/ligand species, while computational molecular simulations allowed information to be gained on the metal–ligand coordination. The dependence on ionic strength and the temperature of equilibrium constants were investigated by means of the extended Debye–Hückel model, the classical specific ion interaction theory, and the van't Hoff equations, respectively. [ABSTRACT FROM AUTHOR]

Ethylenediamine-N,N'-disuccinic acid is a biodegradable alternative to EDTA, therefore its use for the sequestration of Ca 2+ , Sn 2+ , Cu 2+ , Zn 2+ and Fe 3+ is analyzed. New data on its binding ability towards these cations were obtained with potentiometric, voltammetric and calorimetric measurements at different ionic strengths and at T = 298.15 K. Real multi-component fluids, namely fresh water, urine, sea water, saliva and blood plasma were chosen as case studies to evaluate the sequestering ability of EDDS in comparison with EDTA. Speciation diagrams were drawn in selected conditions, considering all interactions among the “natural” components of the fluid and those studied in this work, EDDS and EDTA ( c L = 1 mmol dm −3 ) as sequestering agents and the cited metal cations ( c M ∼ 10 −5 mol dm −3 ). The comparison of the sequestering ability of EDDS and EDTA is done using pM and pL 0.5 . In blood plasma the plasma mobilizing index was adopted. It was found that EDDS is a good alternative to EDTA, which tends to bind Ca 2+ and Mg 2+ more than EDDS. In particular, EDTA cannot be used as a sequestrant for Sn 2+ when c Ca > c EDTA . EDDS is more efficient than EDTA at pH < 8, particularly in urine, where carbonate is absent. In sea water, the sequestering ability of EDDS towards Fe 3+ is higher than that of EDTA. In blood plasma, the PMI of EDDS towards Cu 2+ is higher than that of EDTA. Thermodynamic information, in terms of Δ H and Δ S , for the protonation and metal complex formation reactions are reported. [ABSTRACT FROM AUTHOR]

Abstract: Tin(II) interaction with different phosphate ligands, namely phosphate (PO4), pyrophosphate (PP), tripolyphosphate (TPP), monofluorophosphate (MFP) and adenosine-5′-triphosphate (ATP), was studied at T=298.15K by potentiometry and voltammetry at different ionic strengths (0.15≤ I/molL−1 ≤1.00) in NaNO3. We also compared our results with those experimentally determined for the Zn/PO4 and Zn/TPP systems. As concerns the Zn/PP, the Zn/ATP and the Zn/MFP systems, we performed a critical literature analysis. In all cases the stability constants observed for the Sn/L species resulted to be higher with respect to the analogous Zn/L ones. The rough correlation (valid for the ML species) log K ML (Sn)=3.01·log K ML (Zn)−8.13 was obtained from the stability data of the complexes of these cations. In addition, the stability trend found for a given metal cation was: PP~PO4 >>TPP>>MFP~ATP. The ionic strength dependence of the stability constants was studied by the extended Debye–Hückel and the SIT (Specific ion Interaction Theory) equations. Speciation and sequestration studies were also performed, and pL0.5 values (i.e., the total ligand concentration necessary to bind 50% of cation present in trace) were calculated for all the systems at different pH and ionic strengths. In this case, as an example at pH=7.0 and I =0.15molL−1, the sequestration trend was: PO4 >PP~MFP>>TPP>ATP. The dependence of pL0.5 values on pH and ionic strength was modeled by means of two empirical relationships. [Copyright &y& Elsevier]

Abstract A new polyaminocarboxylic bis-(3-hydroxy-4-pyridinone), derivative of DTPA, DTPA(PrHP) 2 , was synthesized starting from maltol by means of a coupling reaction of a protected 3-hydroxy-4-pyridinone and DTPA bis-anhydride. The DTPA(PrHP) 2 acid-base behavior was investigated by UV–Vis spectrophotometry and spectrofluorimetry at I = 0.15 mol L−1 in NaCl (aq) at T = 298.15 K and T = 310.15 K. To confirm the speciation scheme, also 1H NMR measurements were performed at T = 298.15 K. The protonation constants obtained from the cited different analytical techniques showed good accordance and were also in agreement with data reported in the literature. The complexing ability of DTPA(PrHP) 2 towards divalent (Ca2+, Cu2+, Zn2+) and trivalent (Al3+, Fe3+) cations was studied by potentiometric, UV–Vis spectrophotometric and 1H NMR titrations at T = 298.15 K and I = 0.15 mol L−1 in NaCl (aq). The fitting analysis of experimental data led to the determination of different speciation models consisting of M p L q H r (pn+r-5q) species with different stoichiometry and protonation stages, hydrolytic mixed and polynuclear complexes. The equilibrium model and complex formation constants, obtained from various analytical techniques, are in good agreement. The sequestering ability of the ligand towards the metal cations was assessed through the determination of the pL 0.5 and pM parameters at different pH values and pH = 7.4, respectively, which showed to follow the trend Fe3+ > Al3+ > Cu2+ > Ca2+ > Zn2+. Finally, biodistribution studies were carried out in mice previously injected with the radiotracer 67Ga–citrate to evaluate the in vivo ability of DTPA(PrHP) 2 as chelating agent towards trivalent metal cations. Graphical abstract Metal chelation capacity based on the pM values calculated vs. pH for different Mn+/bis-3-hydroxy-4-pyridinone (DTPA(PrHP) 2) systems; in vivo M3+ sequestration. Unlabelled Image Highlights • A new polyaminocarboxylic bis-(3-hydroxy-4-pyridinone), derived from diethylenetriaminepentaacetic acid, was synthesized. • Its acid-base behavior and complexation towards M2+ and M3+ were investigated. • The sequestering ability of the ligand towards Mn+ was studied using the pL 0.5 parameter determination at different pHs. • The pM values, calculated at physiological pH, follows the trend: Fe3+ > Al3+ > Cu2+ > Ca2+ > Zn2+. • Biodistribution studies indicated that the ligand has high in vivo chelating ability towards trivalent metal cations. [ABSTRACT FROM AUTHOR]

Abstract A new bis-(3-hydroxy-4-pyridinone) ligand (NTA(PrHP) 2), derived from nitrilotriacetic acid (NTA), was synthesized and evaluated for its selective solution metal complexation capacity as well as its in vivo sequestering power for hard metal cations. After the study of its acid-base properties and determination of the protonation constants, the binding ability of NTA(PrHP) 2 towards divalent (Ca2+, Cu2+, Zn2+) and trivalent (Al3+, Fe3+) metal cations was investigated by means of UV–Vis spectrophotometric, potentiometric and 1H NMR measurements. The determined speciation models consist of M p L q H r species with different stoichiometry. The obtained stability constants for the M L species follow the trend: Fe3+ > Al3+ > Cu2+ > Zn2+ > Ca2+. Furthermore, the sequestering ability of the ligand towards these metal cations was investigated by the determination of the pL 0.5 and pM parameters calculated at different pHs and pH = 7.4, respectively. High pL 0.5 values were obtained with significant variation of the sequestering ability with the investigated pH range. Analysis of the pM values at pH = 7.4 showed that the metal-ligand affinity follows the trend: Fe3+ > Al3+ > Cu2+ > Zn2+ > Ca2+. Finally, in vivo assays were performed to verify the efficacy of NTA(PrHP) 2 as sequestering agent towards trivalent metal cations, when administered to mice preloaded with the radiotracer 67Ga–citrate. Graphical abstract A new bis-(3-hydroxy-4-pyridinone) ligand, NTA(PrHP) 2 , with illustration of the its metal chelation capacity and selectivity based on the pM values calculated vs. pH for the different Mn+/ligand systems (a, Ca2+ = Image 4 , Cu2+ = Image 3 , Zn2+ = Image 2 , Al3+ = Image 1 , Fe3+ = ○) and its in vivo excretion capacity in animal model (mice overload with 67Ga) (b). Unlabelled Image Highlights • A new bis-(3-hydroxy-4-pyridinone) ligand derived from nitrilotriacetic acid was synthesized. • Its acid-base properties and binding ability towards M2+ and M3+ were investigated. • The sequestration of the ligand towards Mn+ was studied by the determination of pL 0.5 values at different pHs. • Analysis of pM values at pH = 7.4 showed that the metal-ligand affinity follows the trend Fe3+ > Al3+ > Cu2+ > Zn2+ > Ca2+. • Bioassays indicated that the ligand has high in vivo chelating ability towards trivalent metal cations. [ABSTRACT FROM AUTHOR]

This paper reports the results on the study of a set of synthesized bifunctional 3-hydroxy-4-pyridinones chelators as potential aluminium sequestering agents. They were N -functionalized with alkyl-amino, -carboxylic and –(amino-carboxylic) groups, envisaging the improvement of the Al 3+ sequestering capacity, in comparison with the marketed chelating drug deferiprone. The main focus of this work was given to the assessment of their binding ability towards Al 3+ , which was studied by potentiometric and UV–Vis spectrophotometric measurements carried out at T  = 298.15 K. The speciation models were characterized by Al p L q H r (3p+r−qz) species with different stoichiometry. Depending on ligand side-chain structures and on their thermodynamic properties, different trends of stability was found. Furthermore, the sequestering ability of the ligands towards Al 3+ was investigated by the calculation of pL 0.5 values at different experimental conditions. These results clearly indicate that the presence of amino-carboxylic groups in the ligands increases the sequestering ability towards Al 3+ . The in silico evaluation of pharmacokinetic descriptors indicated no violation to the Lipinski's rule and drug-likeness properties. Furthermore, the in vivo bioassays on a model of metal-overload mice showed for three investigated ligands a higher metal-sequestering capacity than for the chelating drug deferiprone, thus suggesting their potential interest as Al-chelating drug candidates. [ABSTRACT FROM AUTHOR]