Judite Costa

Dissociation constants of Br∅nsted acids in D2O and H2O: studies on polyaza and polyoxa-polyaza macrocycles and a general correlation

Abstract Using data on a series of polyaza and polyoxa-polyaza macrocyclic compounds, a satisfactory linear correlation was established between the dissociation constants of their acid forms obtained in deuterium oxide (p K D ) and in water (p K H ). The isotopic effect, Δp K =p K D - p K H , increases with increasing p K , being larger for the weaker acids. The p K D vs. p K H correlation may be used to determine p K D or p K H values when one of the constants is known; the statistical errors of the estimates are not significatively higher than those of the experimental determinations. By including data available in the literature for a series of different acids (mineral and carboxylic acids, phenols, protonated amines, amino acids, etc.; a total of 138 pairs of data for 70 different compounds), a good general p K D vs. p K H correlation was also obtained (correlation coefficient 0.998), showing that the dependence of the isotopic effect on the nature of the acid is not as important as previous studies, based on limited and not always satisfactory Δp k vs. p K H correlations, suggested.

153Sm and 166Ho complexes with tetraaza macrocycles containing pyridine and methylcarboxylate or methylphosphonate pendant arms

A set of tetraaza macrocycles containing pyridine and methylcarboxylate (ac3py14) or methylphosphonate (MeP2py14 and P3py14) pendant arms were prepared and their stability constants with La3+, Sm3+, Gd3+ and Ho3+ determined by potentiometry at 25xa0°C and 0.10xa0M ionic strength in NMe4NO3. The metal:ligand ratio for 153Sm and 166Ho and for ac3py14, MeP2py14 and P3py14, as well as the pH of the reaction mixtures, were optimized to achieve a chelation efficiency higher than 98%. These radiocomplexes are hydrophilic and have a significant plasmatic protein binding. In vitro stability was studied in physiological solutions and in human serum. All complexes are stable in saline and PBS, but 20% of radiochemical impurities were detected after 24xa0h of incubation in serum. Biodistribution studies in mice indicated a slow rate of clearance from blood and muscle, a high and rapid liver uptake and a very slow rate of total radioactivity excretion. Some bone uptake was observed for complexes with MeP2py14 and P3py14, which was enhanced with time and the number of methylphosphonate groups. This biological profile supports the in vitro instability found in serum and is consistent with the thermodynamic stability constants found for these complexes.

Protonation and metal complexation studies on some oxa-diaza macrocyclic ligands

Abstract Some 9- and 10-membered oxa-diaza macrocyclic ligands and their N-acetate derivatives have been synthesized and their protonation patterns studied by 1 H NMR and potentiometric techniques. The stability constants of the complexes formed by these ligands with several alkaline-earth and first-series transition metal ions, zinc, cadmium and lead, were determined by potentiometry and the values were compared with those formed with the analogous 9-membered tri-aza macrocyclic ligands and with 12-membered oxa-triaza ligands. The substitution of one nitrogen by an oxygen atom in the backbone of the macrocyclic ring has pronounced effects both on the kinetics of the complexation reactions (faster equilibration) and on the stability of the metal complexes formed (decreased stability). The differences in this last case are analysed for two pairs of cyclic amines ([9]aneN 3 /[9]aneN 2 O and [12]aneN 4 /[12]aneN 3 O) with the first transition metal ions and for the corresponding N-acetate derivatives with the first transition and alkaline-earth metal ions.

Activity against Mycobacterium tuberculosis with concomitant induction of cellular immune responses by a tetraaza-macrocycle with acetate pendant arms

The novel tetraaza-macrocyclic compound 3,7,11-tris(carboxymethyl)-3,7,11,17-tetraaza-bicyclo[11.3.1]heptadeca-1(17),13,15-triene, abbreviated as ac3py14, was investigated for its activity against Mycobacterium tuberculosis and for induction of protective cellular immune responses. Perspective results show that ac3py14 and its Fe3+ 1:1 complex, [Fe(ac3py14)], inhibited radiometric growth of several strains of M. tuberculosis. Inhibition with 25 microg/mL varied from 99% for H37Rv to 80% and above for multiple drug-resistant clinical isolates. The capacity of ac3py14 to elicit a beneficial immune response without cellular apoptosis was assessed and compared to the effects of virulent M. tuberculosis. The present study produces evidence that after stimulation with ac3py14 there was significant production of interferon gamma (IFN-gamma), whereas the production of interleukin-5 (IL-5) remained low, and there was development of a memory population (CD45RO). The level of binding of Annexin V, a marker of apoptosis, was not sufficient to result in toxic effects toward alphabeta and gammadelta T cells and CD14+ macrophages. This preliminary study is the first report of a compound that simultaneously exerts an inhibitory effect against M. tuberculosis and induces factors associated with protective immune responses.

Tetraazamacrocycle bearing quinoline pendant arms and its complexation properties

AbstractA new tetraazamacrocycle containing two 5-chloro-8-hydroxyquinoline side arms, L 1 , was synthesized. The protonationconstants of L 1 and the stability constants of its complexes with Cu 2 ,Zn 2 ,Cd and Pb were determined by potentiometric orspectrophotometric methods, at 20 8C in methanol:water (5:1, v/v) and ionic strength 0.10 mol dm 3 in tetrabutylammonium nitrate(TBAN). Compound L 1 has three high protonation constants, the most basic centres being both phenolates of the arms. Mono- anddinuclear complexes were found in solution for all the metal ions, the complexes of copper are thermodynamically very stable, andthe dinuclear complexes of lead(II) are the predominant species even in 1:1 mixtures. UV / Vis spectra of some complexes and EPRof the copper ones confirmed the presence of dinuclear complexes.# 2003 Elsevier B.V. All rights reserved. Keywords: Tetraazamacrocycle; Stability constants; Dinuclear complexes; EPR copper complexes; 8-Hydroxyquinolinyl groups 1. IntroductionMacrocycles containing quinoline side arms havefound many applications as analytical reagents inabsorption spectrophotometry, fluorometry, solvent ex-traction, and partition chromatography [1,2]. Thesecompounds are also used as pesticides [2].The 8-hydroxyquinoline (HQ) forms a stable five-membered chelate ring with metal centres and verystable complexes with divalent transition and post-transition metal ions of the type M(HQ) , M(HQ)

Metal Complexes of an Oxatriaza Macrocycle Containing Pyridine: Thermodynamic Stability and Structural Studies

Abstract A new 14-membered oxatriaza macrocycle containing pyridine has been synthesized, 7-oxa-3,11,17-triazabicyclo[11.3.1]heptadeca-1(17),13,15-triene, L1. The protonation constants of this compound and stability constants of its complexes with the Mn2+ to Zn2+, Cd2+, and Pb2+ were determined by potentiometric methods at 25°C and ionic strength 0.10 Mol dm−3 in KNO3. L1 presents two high values of protonation constants, and the third is very low. Its overall basicity is low because the three basic centres are in close proximity. Only mononuclear complexes were found, and the stability constants with all the metal ions studied are of the same order as those of the corresponding complexes of the oxatriaza macrocycle L2 (1-oxa-4,8,12-triazacyclotetradecane), but lower than those of tetraaza macrocycles of similar or lower cavity size. The electronic spectra together with the values of magnetic moments of the cobalt(II) and nickel(II) complexes of L1 suggest that five co-ordinate species are formed in aqueous solution. The EPR spectroscopy of frozen solutions of the copper(II) complex of L1 has shown only one species characteristic of rhombic symmetry with elongation of the axial bonds and a d x 2-y 2 ground state, and the analysis of the EPR parameters suggests the presence of a bis complex containing two macrocyclic units. The single crystal structure of the complex [CuL1Cl]ClO4 1 was determined. The complex crystallises in the triclinic system, space group P 1, a = 7.4973(9), b = 9.649(2), c = 12.712(2) Å, β = 111.02(2), β = 96.65(1), γ = 90.11(1)°, Z = 2, Dcalcd = 1.691 g cm−3. Final R and R values of 0.0578 and 0.1454 for 2603 reflections with I>2[sgrave](I) and 0.0782 and 0.1619 for all data were obtained. The complex displays a distorted square pyramidal co-ordination sphere, the three nitrogen atoms of the macrocycle and one chlorine atom determining the basal plane and the apical position occupied by the oxygen atom of the macrocyle. The metal centre is 0.275(2) Å away from the N3Cl plane towards to the apical ligand giving rise to a Cu-O bond length of 2.247(4) Å. To achieve this geometric arrangement the oxatriaza macrocycle folds about the line defined by the nitrogen atoms contiguous to the pyridine ring leading to a dihedral angle of 72.2(2)°. The single crystal presents a 1-D centrosymmetric supramolecular structure formed by two chains of cations and anions linked by hydrogen bonding via N-H…O and C-HΔ+δOΔ− intermolecular interactions.

X-Ray diffraction and molecular mechanics studies of 12-, 13-, and 14-membered tetraaza macrocycles containing pyridine: effect of the macrocyclic cavity size on the selectivity of the metal ion

The single crystal structures of complexes [CuL1Br]ClO41, [CuL2Br]PF62, and [NiL2][ClO4]23 were determined (L1 is 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene and L2 is 3,6,10,16-tetraazabicyclo[10.3.1]hexadeca-1(16),12,14-triene). The asymmetric unit of 1 contains two [CuL1Br]+ cations having different five-co-ordinated environments. One (A) exhibits a distorted square pyramidal arrangement, with the basal plane defined by three nitrogen atoms of the macrocycle and the bromine, and the apical position occupied by the nitrogen opposite to the pyridine ring. In the other (B) the donor atoms are distorted from this geometry towards a trigonal bipyramid with the equatorial plane formed by two nitrogen atoms of the macrocycle and Br, and the axial positions occupied by the nitrogen atoms contiguous to the pyridine ring. The complex cation [CuL2Br]+2 exhibits a distorted square pyramidal environment with the basal plane defined by the four nitrogen atoms of the macrocycle and the apical co-ordination by the bromine atom. In [NiL2]2+3 the four nitrogen atoms of the macrocycle form a distorted square planar environment around the nickel centre. Molecular mechanics calculations are used to determine the best-fit sizes for metal ions accommodated into L1 and L2 by evaluation of all sterically allowed conformers for five-co-ordination geometry. The results obtained, together with those of L3 (3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene), published previously, clearly establish the effect of macrocyclic cavity size on metal ion selectivity. These macrocycles prefer a planar conformation to accommodate small metal ions but folded conformations are preferred for longer M–N distances. The increase of the macrocyclic cavity size leads to an increase of the M–N(sp3) distances at which the folded conformer(s) become the most stable form: 1.90, 2.14 and 2.18 A for 12-, 13- and 14-membered macrocycles, respectively.

Metal complexes of dipyridine hexaaza macrocycles. Structural differences between 18- and 20-membered macrocycles on complexation

The hexaaza macrocycles 3,6,14,17,23,24-hexaazatricyclo[17.3.1.18,12]tetracosa-1(23),8,10,12(24),19,21-hexaene ([18]py2N4) and 3,7,15,19,25,26-hexaazatricyclo[19.3.1.19,13]hexacosa-1(25),9,11,13(26),21,23-hexaene ([20]py2N4) were synthesised. The protonation constants of both compounds and the stability constants of their complexes with a wide range of metal ions (Mn2+, Ni2+, Cu2+, Zn2+, Cd2+, Pb2+, Mg2+, Ca2+, Ba2+, La3+ and Gd3+) were determined at 25 °C with ionic strengths of 0.10 mol dm−3 in KNO3. The overall basicity of [20]py2N4 is 3.20 log units larger than that of [18]py2N4 due to the weaker repulsion between the contiguous protonated ammonium sites, which are separated by propyl chains in [20]py2N4 rather than ethyl chains in [18]py2N4. The stability constants of complexes of each metal decrease as the cavity size of the macrocycle is increased, taking into account the difference in basicity of the ligands; the values for the Cu2+, Ni2+ and Zn2+ complexes of both ligands are exceptionally high. Single crystal structures of complexes [Ni([18]py2N4)](ClO4)2·2CH3CN (1), [Cu([18]py2N4)](ClO4)2·2CH3CN (2), [Co([20]py2N4)][Co(H2O)6]0.5(SO4)2·CH3OH·4H2O (3), [Ni([20]py2N4)](ClO4)2(4) and [Cu([20]py2N4)](ClO4)2 (5) were determined. In all complexes, the metal centre exhibit a hexaco-ordinate environment and the macrocycle adopts a twisted helical topology. The effect of the cage sizes of [18]py2N4 and [20]py2N4 on the molecular dimensions of metal complexes of both macrocycles is evaluated and a significant decrease in the helicity is observed in complexes of the 18-membered macrocycle compared to complexes of the 20-membered ring. The X-ray structural results, together with molecular mechanics calculations and NMR studies performed for metal complexes of both macrocycles, indicate that both ligands have enough flexibility to encapsulate smaller and larger metal ions, although it is clear that [20]py2N4 is more flexible than [18]py2N4.