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Silvio Aime

Publications and source records attributed to Silvio Aime.

At least 73 records · Page 4Linked to original sources
PubMed2002

Heterodinuclear Ln[bond]Na complexes with an asymmetrical macrocyclic compartmental Schiff base.

Heterodinuclear lanthanide(III)-sodium(I) complexes [LnNa(L)(Cl)(2)(CH(3)OH)] (Ln=La[bond]Nd, Sm[bond]Lu), where H(2)L is a [1+1] asymmetric compartmental macrocyclic ligand containing a N(3)O(2) Schiff base and a O(3)O(2) crown-ether-like coordination site, have been prepared and characterized by IR, (1)H, (13)C, and (23)Na NMR spectroscopy, mass spectrometry, and electron microscopy. In the solid state, the lanthanide(III) ions coordinate the Schiff-base N(3)O(2) site, and the sodium ion occupies the O(3)O(2) crownlike cavity, as shown by the X-ray crystal structures of the Nd, Eu, Gd, and Yb derivatives. In these complexes, the lanthanide(III) ion is coordinated by two chlorine atoms in the trans position and by three nitrogen and two negatively charged phenol oxygen atoms of the Schiff base, and the ion is heptacoordinated with a pentagonal bipyramidal geometry. The sodium ion is coordinated by three etheric oxygen atoms and the two phenolic oxygens that act as a bridge. A methanol molecule is also coordinated in the apical position of the resulting pentagonal pyramidal polyhedron. A detailed (1)H and (13)C NMR study was carried out in CD(3)OD for both diamagnetic and paramagnetic heterodinuclear complexes [LnNa(L)(Cl)(2)(CH(3)OH)]. The complexes are also isostructural in solution, and their structures parallel those found in the solid state. Moreover, some significative distances determined in the solid state and in solution are comparable. Finally, the potential use of these complexes as molecular probes for the selective recognition of specific metal ions has been tested. In particular, their ability to act as shift reagents and the selectivity of the O(3)O(2) site towards Li(+), Ca(2+), and K(+) were investigated by (23)Na NMR spectroscopy.

Journal Article↗
PubMed2002

A paramagnetic MRI-CEST agent responsive to lactate concentration.

A paramagnetic Yb(III) complex bearing six exchangeable amide protons, [Yb(MBDO3AM)](3+), has been investigated with the aim of developing a MRI-CEST (chemical exchange saturation transfer) contrast agent responsive to the concentration of L-lactate. The complex binds the substrate quantitatively to yield [Yb(MBDO3AM)L-lactate](2+). The exchange between the free and the L-lactate-bound complex is slow on the NMR time scale, and the resonances of their corresponding amide protons are sufficiently separated (more than 10 ppm) to allow their selective irradiation. Therefore, the CEST properties of the two forms can be independently assessed. In turn, the resulting saturation transfer to the bulk water signal is dependent on the L-lactate concentration.

Contrast Media↗
PubMed2002

NMR conformational analysis of antide, a potent antagonist of the gonadotropin releasing hormone.

Antide is a decapeptide [(N-Ac-D-Nal(1)-D-Cpa(2)-D-Pal(3)-Ser(4)-Lys(Nic)(5)-D-Lys(Nic)(6)-Leu(7)-Ilys(8)-Pro(9)-D-Ala(10)-NH(2)] that acts in vivo as an antagonist of GnRH (gonadotropin-releasing hormone). The conformational behavior of antide has been studied in water, TFE, DMF, and DMSO solutions by means of 2D-NMR spectroscopy and molecular dynamics calculations. Antide adopts in aqueous solution a delta-shaped backbone conformation, which is characterized by an irregular turn around residues D-Pal(3)-Ser(4) and by the close spatial proximity of the side chains belonging to D-Nal(1) and Ilys(8) (as many as 17 NOE peaks were detected between these side chains). The side-chain protons of Ilys(8) (especially the H(gamma) ones) present remarkably upfield shifted resonances, because of ring current effects induced by the naphthyl moiety. The upfield shifted resonances of the Ilys(8) H(gamma) hydrogen atoms are strictly characteristic of the water delta-shaped conformation and can be considered as structure markers. The observation of ring current shifted Ilys(8) H(gamma) resonances under different conditions (temperature, pH, solvent) indicates a remarkable stability of the water delta-shaped conformation. Such a conformation is at least partially disrupted in solvent mixtures containing high percentages of organic solvents. TFE can induce a well-defined conformation, which is characterized by an S-shaped backbone conformation. In DMF and DMSO solution, the molecule is basically endowed with a random coil conformation and high fluxionality. Antide fulfills the conformational requirements that are known to play a crucial role in receptor recognition, namely (i) the presence of a turn in the backbone and (ii) the all-trans nature of peptide bonds. In addition, the structural rigidity of antide likely adds a further contribution to the receptor binding affinity.

Dimethyl Sulfoxide↗
PubMed2002

Molecular dynamics simulation of [Gd(egta)(H(2)O)](-) in aqueous solution: internal motions of the poly(amino carboxylate) and water ligands, and rotational correlation times.

Molecular dynamics simulations of [Gd(egta)(H(2)O)](-) (egta(4-)=3,12-bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecanedioate(4-)) have been performed without any artificial constraint on the first coordination sphere, such as covalent bonds between the Gd(3+) and the coordination sites. Two new crystallographic structures were determined for this gadolinium chelate and used to start two molecular dynamics simulations. [Gd(egta)(H(2)O)](-) and [Gd(egta)](-) were both observed during the simulations, with a mean volume for the reaction of dissociation [Gd(egta)(H(2)O)](-)-->[Gd(egta)](-)+H(2)O of +7.2 cm(3)mol(-1), which corroborates the previously published experimental value of +10.5 cm(3)mol(-1). Changes in the conformation of the complex with the inversion of several dihedral angles are observed in the simulations independently from the water dissociation. Very fast changes of the third-order rotation axis direction of the Gd(3+) coordination polyhedron (of symmetry D(3h)) are observed during the simulations and are related to the mechanism of electronic relaxation of the complex. Different rotational correlation times (tau(R)) were calculated from the simulations on various observables of the complex. Protons of the inner sphere have different tau(R). The mean tau(R) of the two Gd-HW(HW=hydrogen of water molecule) vectors is 72% lower than tau(R) of the complex, and 75% lower than tau(R) of the vector Gd-OW (OW=oxygen of water molecule). This discrimination of the tumbling rates should be taken into account in future global (17)O NMR, EPR and NMRD (nuclear magnetic relaxation dispersion) data analysis.

Journal Article↗
PubMed2002

A paramagnetic probe to localize residues next to carboxylates on protein surfaces.

It is shown that the paramagnetic properties of lanthanides can be exploited to obtain information on specific parts of a protein surface. Owing to the high affinity of coordinatively unsaturated lanthanide complexes for oxygen donors, carboxylate groups can be used as preferential targets for the interaction. The DO3A ligand is particularly useful in these studies, as it coordinates lanthanides in a heptadentate fashion, leaving two sites available for exogenous donors. A solution of a (15)N-labeled sample protein, calbindin D(9k) (75 residues), was titrated with up to 200% of Gd(III)-DO3A complex, and an inversion recovery (15)N-(1)H HSQC experiment was used to measure the paramagnetic contributions to the longitudinal relaxation rates of the amide protons. Relaxation data were used as distance constraints to estimate the number of interacting complexes and the occupancies of their binding sites. Four preferential interaction sites on the protein surface are found. Inspection of the various carboxylate side chains on the surface of the protein indicates that Gd(III)-DO3A interacts preferentially with carboxylate-rich regions, rather than with isolated carboxylates, suggesting the possibility of chelation of one Gd(III)-DO3A molecule by two carboxylate groups. Gd(III)-DO3A is thus a valuable semi-selective probe for clusters of negative charges on the protein surface.

Algorithms↗
PubMed2002

Innovative magnetic resonance imaging diagnostic agents based on paramagnetic Gd(III) complexes.

Gd(III) complexes are under intense scrutiny as contrast agents for magnetic resonance imaging (MRI). They act by enhancing tissutal proton relaxation rates. Much has already been done in order to get an in-depth understanding of the relationships between structure, dynamics, and contrastographic ability of these paramagnetic complexes. Their potential in the assessment of flow, perfusion, and capillary permeability has already been established. The next challenges are in the field of molecular imaging applications, which would allow the attainment of early diagnosis based on the recognition of specific reporters of the onset of the pathological state. To this end, Gd(III) complexes have to be endowed with improved targeting capabilities by conjugating suitable recognition synthons on their surfaces. Small peptides are candidates of choice for the attainment of this goal. Moreover, the intrinsic low sensitivity of the NMR techniques implies the need to deliver large amounts of contrast agents to the target in order to get its visualization in the resulting images. Highly efficient delivery systems have been identified, which bring a great promise for the development of innovative diagnostic agents based on Gd(III) complexes.

Chelating Agents↗
PubMed2002

Insights into the use of paramagnetic Gd(III) complexes in MR-molecular imaging investigations.

Can gadolinium III [Gd(III)] complexes be considered good candidates for magnetic resonance (MR)-molecular imaging studies? In this review article, we examine the principal issues that are the basis of successful use of Gd-based protocols in molecular imaging applications. High relaxivity is the primary requisite. Therefore, the design of such paramagnetic probes has to be pursued keeping in mind the relationships between structure, dynamics, and the relevant parameters involved in paramagnetic relaxation processes. Moreover, the limited number of target molecules on cellular membranes makes it necessary to define strategies aimed at delivering many Gd-containing moieties to the sites of interest. Examples are reported for the attainment of very high relaxivities for the design of new routes for pursuing the accumulation of small sized Gd(III) complexes at the targeting sites. An efficient cellular uptake of Gd-containing probes is the key step for attaining the visualization of targeted cells by MR imaging, and selected examples are reported. In this context, the problem of the assessment of the minimum amount of Gd(III) complexes necessary for the MR imaging-visualization of cells has been addressed by reporting the authors' observations on the cell-internalization of Gd(III) complexes. A particularly efficient delivery system is represented by Gd-loaded apoferritin, which allows the MR visualization of hepatocytes when the number of Gd-complexes per cell is 4 +/- 1 x 10(7). Finally, the potential of responsive systems is considered by outlining the exploitation of the amplification effect brought about by the action of a specific enzymatic activity on the relaxivity of a suitably functionalized Gd(III) complex.

Animals↗
PubMed2002

Separation of intra- and extracellular lactate NMR signals using a lanthanide shift reagent.

This work describes the use of [Pr-DO3A] as a shift reagent for differentiating intra- and extracellular L-lactate resonance in (1)H- and (13)C-NMR spectra. DO3A acts as heptadentate ligand towards lanthanide(III) ions, leaving two coordination vacancies for the coordination of the L-lactate ion. The exchange between free and [Pr-DO3A]-bound L-lactate is fast on the NMR timescale, thus yielding a paramagnetically shifted L-lactate signal for the substrate in the compartment containing the paramagnetic chelate. The evaluation of the method was carried out on a model system based on sealed ghosts from human red blood cells.

Acetates↗
PubMed2002

Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications.

The recently introduced new class of contrast agents (CAs) based on chemical exchange saturation transfer (CEST) may have a huge potential for the development of novel applications in the field of MRI. In this work we explored the CEST properties of a series of Lanthanide(III) complexes (Ln = Eu, Dy, Ho, Er, Tm, Yb) with the macrocyclic DOTAM-Gly ligand, which is the tetraglycineamide derivative of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). These complexes possess two pools of exchangeable protons represented by the coordinated water and the amide protons. Yb-DOTAM-Gly displays the most interesting CEST properties when its amide N-H resonance (16 ppm upfield H2O signal) is irradiated. Up to 70% suppression of the water signal is obtained at pH 8. As the exchange rate of amide protons is base-catalyzed, Yb-DOTAM-Gly results to be an efficient pH-responsive probe in the 5.5-8.1 pH range. Moreover, a ratiometric method has been set up in order to remove the dependence of the observed pH responsiveness from the absolute concentration of the paramagnetic agent. In fact, the use of a mixture of Eu-DOTAM-Gly and Yb-DOTAM-Gly, whose exchangeable proton pools are represented by the coordinated water (ca. 40 ppm downfield H2O signal at 312K) and amide protons, respectively, produces a pH-dependent CEST effect which is the function of the concentration ratio of the two complexes.

Chelating Agents↗
PubMed2002

Binding and relaxometric properties of heme complexes with cyanogen bromide fragments of human serum albumin.

The spectroscopic and reactivity properties of hemin complexes formed with cyanogen bromide fragments B (residues 1-123), C (124-298), A (299-585), and D (1-298) of human serum albumin (HSA) have been investigated. The complex hemin-D exhibits binding, spectral, circular dichroism, and reactivity characteristics very similar to those of hemin-HSA, indicating that fragment D contains the entire HSA domain involved in heme binding. The characteristics of the other hemin complexes are different, and a detailed investigation of the properties of hemin-C has been carried out because this fragment contains the HSA binding region of several important drugs. Hemin-C contains a low-spin Fe(III) center, with two imidazole ligands, but the complex undergoes a reversible structural transition at basic pH leading to a high-spin, five-coordinated Fe(III) species. This change determines a marked increase in the relaxation rate of water protons. Limited proteolysis experiments and mass spectral analysis carried out on fragment C and hemin-C show that the region encompassing residues Glu-208 to Trp-214 is protected from activity of proteases in the complex and, therefore, is involved in the interaction with hemin. A structural model of fragment C enables us to propose that His-242 and His-288 are the axial ligands for the Fe(III) center.

Binding Sites↗
PubMed2001

Relaxometric evaluation of novel manganese(II) complexes for application as contrast agents in magnetic resonance imaging.

Three novel Mn(II) complexes bearing benzyloxymethyl functionalities are reported and their ability to enhance water (1H and 17O) relaxation times is investigated in detail. Two of them contain one coordinated water molecule and display relaxivity values only slightly smaller than those shown by the most clinically used contrast agents (e.g. [Gd(DTPA)(H2O)]2-). Moreover, in these Mn(II) chelates the exchange rate of the coordinated water is ca. one order of magnitude higher if compared to the exchange rates previously reported for Gd(III) complexes with octadentate ligands. The occurrence of such fast exchange rates of the coordinated water is exploited in the formation of macromolecular adducts with human serum albumin to attain systems displaying relaxivity values in the upper range of those so far reported for analogous Gd(III) systems. These results strongly support the view that Mn(II) complexes, in spite of the lower effective magnetic moment, can be considered as viable alternatives to the currently used Gd(III) complexes as contrast agents for MRI applications.

Chelating Agents↗
PubMed1999

Synthesis, X-ray Structure, and Solution NMR Studies of Ln(III) Complexes with a Macrocyclic Asymmetric Compartmental Schiff Base. Preference of the Ln(III) Ions for a Crown-Like Coordination Site.

The compartmental ligand H(2)L(A), containing an N(3)O(2) Schiff base and an O(2)O(3) crown like coordination site, has been prepared by reaction of 3,3'-(3-oxapentane-1,5-diyldioxy)bis(2-hydroxybenzaldehyde) with 1,5-diamino-3-azamethylpentane. The formation of a [1+1] macrocycle was inferred by IR, NMR, and mass spectrometry. When reacted with the rare-earth hydrate chlorides, LnCl(3).nH(2)O (Ln = La, Ce, Pr, Nd, Eu, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y), H(2)L(A) or its precursors (template reaction) form the mononuclear complexes [Ln(H(2)L(A))(H(2)O)(4)]Cl(3).nH(2)O where the lanthanide ion coordinates the O(2)O(3) crown like site. The solid-state X-ray structures of [Ln(H(2)L(A))(H(2)O)(4)]Cl(3).nH(2)O (Ln = Ce, Dy, Lu) have been determined. [Lu(H(2)L(A))(H(2)O)(4)]Cl(3).3H(2)O is monoclinic space group P2(1)/n (Z = 4) with a = 15.269(5) Å, b = 11.484(5) Å, c = 19.389(6) Å, beta = 102.85(5) degrees; [Ce(H(2)L(A))(H(2)O)(4)]Cl(3).H(2)O and [Dy(H(2)L(A))(H(2)O)(4)]Cl(3).H(2)O are isomorphous, space group P2(1) (Z = 2), with a = 10.959(5) Å, b = 16.978(5) Å, c = 9.017(4) Å, beta = 97.73(5) degrees, and a = 10.874(5) Å, b = 16.797(5) Å, c = 9.046(4) Å, beta = 97.86(5) degrees for the cerium and dysprosium complexes, respectively. In the three compounds the metal ion is coordinated in a similar manner by the five oxygens (two phenolic and three etheric) of the cyclic ligand and the nine coordination around the central atom is reached by the oxygen atoms of four coordinated water molecules. Three chlorine ions are present in the asymmetric unit. A detailed (1)H NMR study was carried out in CD(3)OD for both the diamagnetic and paramagnetic [Ln(H(2)L(A))(H(2)O)(4)]Cl(3) complexes in order to compare their structure in solution with that found in the solid state. The quantitative analysis of the paramagnetic proton shifts indicates that the complexes from La to Tm are isostructural, maintain in solution the same type of coordination polyhedron found at the solid state, with the metal ion invariably coordinated in the O(2)O(3) compartment, and present a high degree of stereochemical nonrigidity. In the case of the Lu complex, the decreased fluxionality due to the reduced ionic radius allows the observation of two isomeric species in the (1)H NMR spectrum at low temperature.

Journal Article↗
PubMed1997

Synthesis and NMR Studies of Three Pyridine-Containing Triaza Macrocyclic Triacetate Ligands and Their Complexes with Lanthanide Ions.

The synthesis of three triazamacrocycles containing the pyridine moiety and three acetate pendant arms (PCTA) is reported. The three systems differ due to the number of carbon atoms in the macrocyclic ring forming ligands PCTA-[12], -[13], and -[14], endowed with different coordination capabilities toward lanthanide(III) ions. Microscopic protonation sequences for the three ligands have been investigated by (1)H NMR spectroscopy. Complexes of PCTA-[12], -[13], and -[14] with La(III), Gd(III), and Lu(III) have been prepared. Relaxometric measurements on the aqueous solutions of the paramagnetic Gd(III) complexes in the presence of competitive ligands gave the following stability constants: log K(f) = 20.8 for Gd-PCTA-[12], log K(f) = 19.3 for GdPCTA-[13], and log K(f) = 12.5 for GdPCTA-[14]. The measurement of water relaxation rates indicated a tendency to decrease the degree of hydration upon increasing the ring size. The VT (1)H and (13)C-NMR spectra of the diamagnetic La(III) and Lu(III) complexes exhibit a large variability of the solution structures dictated by the matching of the size of the lanthanide ion and the macrocyclic cavity. This results in noticeable differences in their stereochemical nonrigidity, hydration state, and thermodynamic stability. To some extent the changes observed in continuing from the 12-14-membered ring macrocyclic complexes parallels the behaviors shown by the octacoordinated lanthanide(III) complexes with DOTA and TETA. GdPCTA-[12] and -[13] feature promising properties in view of their possible use as contrast agents for magnetic resonance imaging.

Journal Article↗
PubMed1997

Conformational and Coordination Equilibria on DOTA Complexes of Lanthanide Metal Ions in Aqueous Solution Studied by (1)H-NMR Spectroscopy.

A variable-temperature, -pressure, and -ionic strength (1)H NMR study of the DOTA complexes of different trivalent cations (Sc, Y, La, Ce --> Lu) (DOTA = 1,4,7,10-tetraaza-1,4,7,10-tetrakis(carboxymethyl)cyclododecane) yielded data that are in contradiction with the hitherto used model of only two enantiomeric pairs of diastereoisomers that differ in the ligand conformations. A two-isomer equilibrium cannot explain the newly observed apparent reversal of the isomer ratio at the end of the series. As both conformers may lose their inner sphere water molecule, a coordination equilibrium may be superimposed on this conformational equilibrium, as shown by large positive reaction volumes for the isomerization of [Ln(DOTA)(H(2)O)(x)()](-) (Ln = Yb, Lu; x = 1, 0). The isomerization of [Nd(DOTA)(H(2)O)](-) and [Eu(DOTA)(H(2)O)](-) is purely conformational, as shown by near-zero reaction volumes. The measured isomerization enthalpies and entropies agree with this model. The shift of the isomerization equilibria by a variety of non-coordinative salts depends on the ligand conformation rather than the presence or absence of the inner sphere water molecule. This results from weak ion binding and water solvent stabilization of one ligand conformation, rather than the decrease of the activity of the bulk water in the solution, as shown by UV-vis measurements of the coordination number sensitive transition (5)F(0) --> (7)D(0) of Eu(III) as a function of ionic strength. Fluoride ions replace a water molecule in the inner coordination sphere, preferentially for one of the conformational isomers, as proven by (19)F-NMR shifts and the appearance of a third set of resonances corresponding to [Eu(DOTA)F](2)(-) in the (1)H-NMR spectrum of [Eu(DOTA)(H(2)O)](-).

Journal Article↗