Pedro Mateus

Polyaza Cryptand Receptor Selective for Dihydrogen Phosphate

A hexaamine cage with pyridyl spacers was synthesized in good yield by a [2+3] Schiff-base condensation followed by sodium borohydride reduction. The protonation constants of the receptor as well as its association constants with Cl(-), NO(3)(-), AcO(-), ClO(4)(-), SO(4)(2-), H(2)PO(4)(-), and H(2)AsO(4)(-) were determined by potentiometry at 298.2 +/- 0.1 K in H(2)O/MeOH (50:50 v/v) and at ionic strength 0.10 +/- 0.01 M in KTsO. These studies revealed that although dihydrogen phosphate is less charged than sulfate, it is still appreciably bound by the receptor at low pH, suggesting that the pyridyl nitrogen is accepting hydrogen bonds from dihydrogen phosphate. It is also shown that dihydrogen phosphate is capable of effectively competing with sulfate for the receptor at higher pH, being selective for hydrogen phosphate at pH about 7.0. (31)P NMR experiments supported these findings. The fact that the receptor shows such a marked preference for hydrogen phosphate based mainly in its hydrogen bond accepting/donating ability in a highly competitive medium such as water/methanol mixed solvent is quite remarkable. Single-crystal X-ray diffraction determinations of anion associations between H(6)pyr(6+) receptor and nitrate, sulfate, and phosphate are consistent with the existence of [(H(6)pyr)(NO(3))(3)(H(2)O)(3)](3+), [(H(6)pyr)(SO(4))(2)(H(2)O)(4)](2+), and [(H(6)pyr)(HPO(4))(2)(H(2)PO(4))(H(2)O)(2)](+) cations. One nitrate anion is embedded into the H(6)pyr(6+) cage of the first supermolecule whereas in the second and third ones the anions are located in the periphery of the macrobicycle.

A Trinuclear Copper(II) Cryptate and Its μ3‐CO3 Cascade Complex: Thermodynamics, Structural and Magnetic Properties

The 2,4,6-triethylbenzene-capped hexaamine macrobicycle with pyridyl spacers (pyr) was able to coordinate three copper(II) ions within its cavity. Potentiometric studies performed at 298.2 K in MeOH/H(2)O (50:50 v/v) and at ionic strength 0.10 mol dm(-3) in KNO(3) revealed that trinuclear species predominate in solution from pH 5.0, the hydroxo complexes being the main species, which start forming at unusual very low pH values. The single-crystal X-ray determination of the trinuclear complex showed that the three copper centres have square-planar geometry, arranged in an almost equilateral triangle, and have carbonate bridging the three metal centres. The presence of carbonate resulted from fixation of atmospheric CO(2). The present study represents the first μ(3)-CO(3)-bridged trinuclear copper(II) complex located in the interior of a macrobicyclic cavity. The magnetic data of [Cu(3)(pyr)(μ(3)-CO(3))]·(ClO(4))(4) showed ferromagnetic intramolecular interactions [J=3.80 cm(-1), based on the Hamiltonian H=-J(S(1)S(2)+S(2)S(3)+S(1)S(3))] yielding a spin quartet, S=3/2, ground state. Density functional calculations on the experimental geometry of the trinuclear complex showed that the ferromagnetic nature of the magnetic coupling can be attributed to the syn-anti conformation of the carbonato bridge, and a magneto-structural correlation, based on the different conformations (syn-anti, syn-syn and anti-anti), is presented. The interesting properties observed, namely the lowering of the pK(a) of coordinated water molecules to unusual values and the good fit of the carbonate anion between the copper centres, derive from the special architecture of pyr.

Dicarboxylate Recognition by Two Macrobicyclic Receptors: Selectivity for Fumarate over Maleate

Two ditopic polyamine macrobicyclic compounds have been studied as receptors for the recognition of dicarboxylate anions of varying chain length in aqueous solution. One of the receptors consists of two tris(2-aminoethyl)amine-derived binding subunits separated by p-xylyl spacers, while the other is a heteroditopic compound, combining two different head units, a tren-derived and a 2,4,6-triethylbenzene-derived one, also separated by p-xylyl spacers. The acid-base behavior of the compounds as well as their binding ability with oxalate (oxa(2-)), malonate (mal(2-)), succinate (suc(2-)), glutarate (glu(2-)), maleate (male(2-)) and fumarate (fum(2-)) anions were studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KTsO. NMR studies were also performed to obtain structural information in solution on the supermolecules formed by association of the protonated macrobicycles with the dicarboxylate substrates. The results revealed that both compounds are able to form stable associations with the dianionic substrates in competitive aqueous solution, with unprecedented selectivity for fum(2-) over other dicarboxylate competitors, including its cis isomer male(2-). In addition it was found that although the selectivity pattern is unaffected by the introduction of the 2,4,6-triethylbenzene head unit, the affinity toward dicarboxylates is significantly reduced. Therefore, the comparison between the binding behavior of these two receptors showed the effect of the increased rigidity and lipophilicity of the receptor with the 2,4,6-triethylbenzene head unit in the binding properties and the selectivity pattern.

Dinuclear Zinc(II) Macrocyclic Complex as Receptor for Selective Fluorescence Sensing of Pyrophosphate

A new diethylenetriamine-derived macrocycle known as L, bearing 2-methylquinoline arms and containing m-xylyl spacers, was prepared in good yield by a one-pot [2 + 2] Schiff base condensation procedure, followed by reduction with sodium borohydride. Up to now this is the first hexaazamacrocycle with appended fluorophore units. Single-crystal X-ray diffraction determination of the dinuclear zinc(II) complex of L showed that metal centers are located at about 7.20(2) Å from one another. This complex exhibits only weak fluorescence in aqueous solution, but the addition of 1 equiv of pyrophosphate (PPi) caused a 21-fold enhancement of the fluorescence intensity. The sensor response is linear up to a value of 10 μM HPPi(3-) and has a detection limit of 300 nM. The receptor behaves as a highly selective sensor for pyrophosphate as other anions, including phosphate, phenylphosphate (PhP), adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP), failed to induce any fluorescence change and practically do not affect the fluorescence intensity of the sensor in the presence of HPPi(3-). Competition titrations carried out in aqueous solution at pH 7.4 [in 20 mM 3-(N-morpholino)propanesulfonic acid (MOPS) buffer] by spectrofluorometry revealed a high association constant value of 6.22 log units for binding of PPi by the dinuclear zinc(II) receptor, one of the highest reported values for colorimetric/fluorometric sensors able to work under real aqueous physiological conditions, while association constant values for binding of the other phosphorylated substrates are in the 5.51-4.03 log unit range.

Dicarboxylate Recognition Properties of a Dinuclear Copper(II) Cryptate

A ditopic polyamine macrobicyclic compound with biphenylmethane spacers was prepared, and its dinuclear copper(II) complex was studied as a receptor for the recognition of dicarboxylate anions of varying chain length in H2O/MeOH (50:50 (v/v)) solution. The acid-base behavior of the compound, the stability constants of its complexes with Cu(2+) ion, and the association constants of the copper(II) cryptate with succinate (suc(2-)), glutarate (glu(2-)), adipate (adi(2-)), and pimelate (pim(2-)) were determined by potentiometry at 298.2 ± 0.1 K in H2O/MeOH (50:50 (v/v)) and at ionic strength 0.10 ± 0.01 M in KNO3. The association constants of the same cryptate as receptor for aromatic dicarboxylate substrates, such as phthalate (ph(2-)), isophthalate (iph(2-)), and terephthalate (tph(2-)), were determined through competition experiments by spectrophotometry in the UV region. Remarkably high values of association constants in the range of 7.34-10.01 log units were found that are, to the best of our knowledge, the highest values of association constants reported for the binding of dicarboxylate anions in aqueous solution. A very well defined peak of selectivity was observed with the binding constant values increasing with the chain length and reaching the maximum for substrates with four carbon atoms between the carboxylate groups. Single-crystal X-ray diffraction determinations of the cascade complexes with adi(2-) and tph(2-) assisted in the understanding of the selectivity of the cryptate toward these substrates. The Hirshfeld surface analyses of both cascade complexes suggest that the establishment of several van der Waals interactions between the substrates and the walls of the receptor also contributes to the stability of the associations.

Cyclen derivatives with two trans-methylnitrophenolic pendant arms: a structural study of their copper(II) and zinc(II) complexes

Two new cyclen derivatives, H(2)do2nph and H(2)cb-do2nph, containing two trans-2-methyl-4-nitrophenol pendant arms and the latter including also an ethylene cross-bridge, were prepared in good yields using the bisaminal synthetic route. The two ligands were studied comparatively regarding their metal complexation behaviour. The copper(II) and zinc(II) complexes of H(2)do2nph and H(2)cb-do2nph were studied in dimethylsulfoxide-water (9 : 1 v/v) solution by a range of spectroscopic techniques. Copper(II) complexes were also studied in solid state by X-ray single crystal diffraction. These studies showed that the copper(II) and zinc(II) complexes of H(2)do2nph exhibited a distorted square pyramidal coordination environment with the four nitrogen atoms of the cyclen ring defining the basal plane, and that one of the nitrophenolate arms did not coordinate to the metal, independently of its protonation state. On the other hand, depending on the protonation state of one of the nitrophenolic arms, the cross-bridged derivative forms copper(II) complexes with distorted square pyramidal or octahedral geometries with one or two arms coordinated to the metal centre, respectively. In the complex with distorted octahedral geometry, the two phenolic oxygen atoms are coordinated to the metal centre in a cis-fashion. Acid-assisted dissociation assays in 1 mol dm(-3) HCl DMSO-H(2)O (9 : 1 v/v) solution at 298.2 K allowed one to determine the half-life of both copper(II) complexes, which is lower for the derivative without a cross-bridge as expected, while for the other one it is quite high and in line with similar cross-bridged cyclen derivatives from the literature.

Di- versus Trinuclear Copper(II) Cryptate for the Uptake of Dicarboxylate Anions

Searching for receptors selective for the binding of dicarboxylate anions, the copper(II) complexes of the known ditopic octaazacryptand (t2pN8), derived from bistren [tren = tris(2-aminoethyl)amine] linked by p-xylyl spacers, were re-examined, with the expectation of observing a selective binding of oxalate or malonate by bridging the two copper centers of the [Cu2(t2pN8)(H2O)2](4+) receptor. Solution studies involving the supramolecular species formed by the receptor and oxalate (oxa(2-)), malonate (mal(2-)), and succinate (suc(2-)) anions are reported. The determined association constants revealed the unexpected formation of a 3:1:1 Cu/t2pN8/anion stoichiometry for the cascade species with oxa(2-) and mal(2-), and the single crystal X-ray structural characterization confirmed the presence of tricopper(II) complexes, with an unusual binding mode for the dicarboxylate anions. Each of the two copper atoms binds four nitrogen donor atoms of the t2pN8 cryptand and one additional hydroxide group, which bridges to the third copper. The square planar environment of this one is complete with two oxygen atoms from the oxalate (or the malonate). The two copper centers bound to the tren heads are ∼6.5 Å apart, each one at about 3.5 Å from the third Cu center. These studies were complemented by SQUID magnetization measurements and DFT calculations. The magnetic susceptibility measurements of the oxalate cascade complex showed a strong magnetic coupling (J = - 210 cm(-1)) between the Cu centers at a short distance (3.5 Å), while the coupling between the two equivalent Cu atoms (∼6.5 Å) was only -70 cm(-1). This result was well reproduced by DFT calculations.

A polyoxapolyaza macrobicyclic receptor for the recognition of zwitterions

A polyoxapolyaza heteroditopic macrobicyclic compound (btpN(4)O(3)) was synthesized. The acid-base behaviour of the compound as well as its binding ability for zwitterionic amino acids were studied by potentiometry at 298.2 ± 0.1 K in H(2)O-MeOH (50:50 v/v) and at I = 0.10 ± 0.01 M in NMe(4)TsO. The H(n)btpN(4)O(3)(n+) showed preference for amino acids containing tetrahedral anionic groups.

Inhibition of the STAT3 Protein by a Dinuclear Macrocyclic Complex.

A new diethylenetriamine-derived macrocycle bearing 2-methylpyridyl arms and containing m-xylyl spacers, L, was prepared, and its dinuclear copper(II) and zinc(II) complexes were used as receptors for the recognition in aqueous solution of a phosphorylated peptide derived from a sequence of the STAT3 protein. A detailed study of the acid-base behavior of L and of its complexation properties as well as of the association of the phosphorylated peptide to the receptor was carried out by potentiometry in aqueous solution at 298.2 K and I = 0.10 M in KNO3. The data revealed that the receptor forms stable associations with several protonated forms of the substrate, with constant values ranging from 3.32 to 4.25 log units. The affinity of the receptor for the phosphorylated substrate studied is higher at a pH value where the receptor is mainly in the [Cu2L](4+) form and the pY residue of the substrate is in the dianionic form (pH 6.55). These results, also supported by (31)P NMR studies, showed that the phosphopeptide is bound through the phosphoryl group in a bridging mode. Additionally, the receptor inhibited binding between active (phosphorylated) STAT3 and its target DNA sequence in a dose-dependent manner (IC50 63 ± 3.4 μM) in human nuclear extracts in vitro. Treatment of whole cells with the inhibitor revealed that it is bioactive in living cells and has oncostatic properties that could be interesting for the fight against cancer and other pathologies involving the STAT3 protein.