Analysis of the conformational behavior and stability of the SAP and TSAP isomers of lanthanide(III) NB-DOTA-type chelates

Controlling the water exchange kinetics of macrocyclic Gd(3+) chelates, a key parameter in the design of improved magnetic resonance imaging (MRI) contrast media, may be facilitated by selecting the coordination geometry of the chelate. The water exchange kinetics of the mono- capped twisted square antiprism (TSAP) being much closer to optimal than those of the mono capped square antiprism (SAP) render the TSAP isomer more desirable for high relaxivity applications. Two systems have been developed that allow for selection of the TSAP coordination geometry in 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd(3+) chelates, both based upon the macrocycle nitrobenzyl cyclen. In this paper we report investigations into the stability and formation of these chelates. Particular focus is given to the production of two regioisomeric chelates during the chelation reaction. These regioisomers are distinguished by having the nitrobenzyl substituent either on a corner or on the side of the macrocyclic ring. The origin of these two regioisomers appears to stem from a conformation of the ligand in solution in which it is hypothesized that pendant arms lie both above and below the plane of the macrocycle. The conformational changes that then result during the formation of the intermediate H(2)GdL(+) chelate give rise to differing positions of the nitrobenzyl substituent depending upon from which face of the macrocycle the Ln(3+) approaches the ligand.     

Investigation of Two Zr-p-NO2Bn-DOTA Isomers via NMR and Quantum Chemical Studies

A combination of NMR studies and quantum chemical calculations were employed to investigate the structure and energetics of Zr⁴⁺ chelates of pNO₂Bn-DOTA. We have demonstrated that two discrete regioisomeric chelates are generated during the complex formation. The nitrobenzyl substituent can adopt either an equatorial corner or side position on the macrocyclic ring. These regioisomers are incapable of interconversion and were isolated by HPLC. The corner isomer is more stable than the side, and the SAP conformer of both regioisomers is energetically more favorable than the corresponding TSAP conformer.     

Towards the rational design of MRI contrast agents: δ-substitution of lanthanide(III) NB-DOTA-tetraamide chelates influences but does not control coordination geometry

LnDOTA-tetraamide chelates (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) have received considerable recent attention as a result of their potential to act as PARACEST contrast agents for magnetic resonance imaging (MRI). Although PARACEST agents afford several advantages over conventional contrast agents they suffer from substantially higher detection limits; thus, improving the effectiveness of LnDOTA-tetraamide chelates is an important goal. In this study we investigate the potential to extend conformational control of LnDOTA-type ligands to those applicable to PARACEST. Furthermore, the question of whether δ- rather than α-substitution of the pendant arms could be used to control the chelate coordination geometry is addressed. Although δ-substitution does influence coordination geometry it does not afford control. However, it can play an important role in governing the conformation of the amide substituent relative to the chelate in such as way that suggests a PARACEST agent could be designed that has detection limits at least as low as a conventional MRI contrast agent.     

Towards the rational design of MRI contrast agents: a practical approach to the synthesis of gadolinium complexes that exhibit optimal water exchange

The gadolinium(iii) complex of S-SSSS-NO(2)BnDOTMA exhibits water exchange kinetics that are optimal for use in high relaxivity or targeted contrast agents. However, the synthesis of this ligand is hampered by the steric encumbrance imparted upon the cyclen ring by the nitrobenzyl substituent. A relatively simple modification has been used to enable the synthesis of larger quantities of a bifunctional ligand that retains similar fast water exchange properties. The gadolinium complex of S-SSS-NO(2)BnDO3MA-1A is shown to retain the rapid water exchange kinetics characteristic of a twisted square antiprismatic (TSAP) coordination geometry (tau(M)= 6 +/- 0.4 ns).     

Liquid adsorption chromatography of chelates : The effect of structure on the thin-layer chromatographic behaviour of chelates

The thin-layer chromatographic behaviour of chelates belonging to different classes is discussed. The major adsorption interactions of chelates are hydrogen bonding between the ligand donor atoms and the surface hydroxyl groups and reactions between the metal atom and the electron-donor active centres of the sorbent. Predominance of either of these general mechanisms depends on the chelate structure and particularly on the coordination saturation of the chelate. Coordination-saturated chelates are retained because of hydrogen bonding, while the metal atom does not participate directly but can influence sorption by affecting the electron density distribution in the chelating ring. Atomic electronegativity is used as a measure of the electron-acceptor ability of the metal. Electronegative atoms located outside the functional group of the chelate can participate in the adsorption either directly or by affecting the proton-acceptor ability of the donor atoms as a result of induction and steric effects. The relationship between chelate retention factors and the parameters characterizing the electron and spatial structure of ligands can be described quantitatively by an equation of the type log [(/R_f)?1] = A + Σσ. In the case of coordination-unsaturated chelates, adsorption interactions with participation of the metal atom predominate, either by ion exchange (with ligand replacement) or by a donor-acceptor mechanism (with introduction of the adsorption centre into the coordination sphere without decomposition). In general, the adsorbability of chelates is directly related to the proton-acceptor ability of donor atoms and the acceptor ability of the metal atom. Classification of chelates by their adsorption interactions is proposed. Recommendations are given for selecting the optimal chelating reagent for the separation of metals by liquid-adsorption chromatography.     

Polymethylated DOTA ligands. 2. Synthesis of rigidified lanthanide chelates and studies on the effect of alkyl substitution on conformational mobility and relaxivity

M4DOTA, [(2S,5S,8S,11S)-4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid (2e), and M4DOTMA, (R)-2-[(2S,5S,8S,11S)-4,7,10-tris-((R)-1-carboxyethyl)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid (3e), are derivatives of ligand DOTA (1e) that form sterically crowded lanthanide chelates. M4DOTMA forms highly symmetric and totally rigid single Y(3+) and Yb(3+) species in which the ring substituents occupy corner positions in a square antiprismatic arrangement as shown by molecular mechanics calculations and by a quantitative interpretation of the relative magnitudes of the paramagnetic (1)H NMR shifts of dipolar origin. The NMR spectrum of YbM4DOTMA(-) displays two intense methyl peaks outside the 0-10 ppm range whose shift difference is strongly temperature dependent. YbM4DOTMA(-) (3d) could be a useful probe in magnetic resonance thermometric imaging. With only four methyl substituents on the tetraaza ring, M4DOTA forms three Yb(3+) species in solution. The methyl substituents prevent the inversion of configuration of the ethylenic groups but not of the acetate arms. Although the methyl groups are likely to preferably occupy ring corner positions, the dipolar equations do not allow one to distinguish with certainty between the two available corner (equatorial) orientations. Reliably applying the dipolar equations is less obvious than usually assumed. A single methyl substituent as in ligand MDOTA (5e) suffices to rigidify the tetraaza cycle but not the acetate arms. Racemic YbMDOTA(-) (5d) is present in solution as four totally asymmetric topomers with the methyl groups occupying either one of the two equatorial positions. A complete assignment of the solution structures on the basis of the dipolar equations is again uncertain. The nuclear magnetic relaxation dispersion curves of the Gd(3+) chelates of all the methylated DOTA ligands including DOTMA, (R)-2-[4,7,10-tris-((R)-carboxyethyl)- 1,4,7,10- tetraazacyclododecan-1-yl]propionic acid, are very similar, and intermolecular conformational processes appear to have no influence on the relaxivity of these small complexes for which the relaxation T(1) is mainly determined by the rotational correlation time (tau(r)). The hydration number of the Tb(3+) chelates measured by fluorescence decreases from DOTMA to M4DOTMA presumably because steric crowding leads to an increase of the metal-water distance.     

Properties, solution state behavior, and crystal structures of chelates of DOTMA

The chemistry of polyamino carboxylates and their use as ligands for Ln(3+) ions is of considerable interest from the point of view of the development of new imaging agents. Of particular interest is the chemistry of the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives. Herein we report that the tetramethylated DOTA derivative, DOTMA, possess several properties that, from an imaging agent development point of view, are more advantageous than those of the parent DOTA. In particular, the Ln(3+) chelates of DOTMA exhibit a marked preference for the monocapped twisted square antiprismatic coordination isomer which imparts more rapid water exchange kinetics on the chelates; τ(M)(298) was determined to be 85 ns for GdDOTMA. Differential analysis of the (17)O R(2ρ) temperature profiles of both GdDOTA and GdDOTMA afforded the τ(M)(298) values for the square (SAP) and twisted square antiprismatic (TSAP) isomers of each chelate that were almost identical: 365 ns (SAP) and 52 ns (TSAP). The origin of this accelerated water exchange in the TSAP isomer appears to be the slightly longer Gd-OH(2) bond distance (2.50 ?) that is observed in the crystal structure of GdDOTMA which crystallizes in the P(2) space group as a TSAP isomer. The Ln(3+) chelates of DOTMA also exhibit high thermodynamic stabilities ranging from log K(ML) = 20.5 for CeDOTMA, 23.5 for EuDOTMA and YbDOTMA comparable to, but a shade lower than, those of DOTA.     

Stereochemistry in functionalized macrocycle complexes: control of hydroxyl substituent orientation

Use of a hydroxyl-functionalized open chain tetramine in a template reaction based on its Cu(II) complex leads, after reduction, to a new tetraaza macrocycle with both amino and hydroxyl substituents. The macrocycle is formed predominantly as its trans (anti) isomer, though the cis form is detectable and both have been structurally characterized in the form of their metal complexes. Although both the Cu(II) and the Co(III) complexes of the tetramine precursor ligand have the hydroxyl group in an axial position of a chair six-membered chelate ring, the trans macrocycle forms Co(III) complexes with this substituent in both equatorial and axial positions.     

Solution dynamics and stability of lanthanide(III) (S)-2-(p-nitrobenzyl)DOTA complexes

Addition of a benzyl substituent to the macrocyclic ring of DOTA has a substantial impact on the conformational ring flipping motion of the macrocycle in the resulting LnDOTA complexes. The p-NO2-benzyl substituent in the Ln(p-NO2-Bn-DOTA)- complexes lies in an equatorial position and effectively "locks" the conformation of the ring into the deltadeltadeltadelta configuration. The presence of the p-NO2-benzyl group also increases the population of the square antiprismatic (SAP) coordination isomer for all Ln(p-NO2-Bn-DOTA)- complexes relative to that seen for the respective LnDOTA- complexes. Despite this increase in SAP isomer population, the rate of water exchange in these complexes remains comparatively fast. The kinetic and thermodynamic stabilities of the Ln(p-NO2-Bn-DOTA)- complexes are also slightly lower than the corresponding LnDOTA- complexes but appear to be sufficiently high for in vivo use.     

Synthesis of areneacetylenic chelate complexes of chromium with a terminal triple bond, their reversible rearrangements to areneallenic chelates, and addition at the triple bond

New areneacetylenedicarbonylchromium chelate complexes containing the terminal acetylene fragment in the side chain of the arene ligand were synthesized. The rearrangement of these chelates to the previously unknown areneallenedicarbonylchromium chelate complexes was found and studied. It was demonstrated that this rearrangement is in principle reversible. For areneallenedicarbonylchromium chelates, a new example of metallotropic rearrangement was found and both isomers, namely, with the coordination either at the substituted or at the nonsubstituted double bond of the allene ligand, were detected for the first time. The coupled addition of the proton and the nucleophile at the coordinated triple bond afforded the corresponding areneolefin chelates. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1168–1175, June, 1999.     

Substituent control of hydrogen bonding in palladium(II)-pyrazole complexes

Inter- and intramolecular hydrogen bonding of an N-H group in pyrazole complexes was studied using ligands with two different groups at pyrazole C-3 and C-5. At C-5, groups such as methyl, i-propyl, phenyl, or tert-butyl were present. At C-3, side chains L-CH(2)- and L-CH(2)CH(2)- (L = thioether or phosphine) ensured formation of chelates to a cis-dichloropalladium(II) fragment through side-chain atom L and the pyrazole nitrogen closest to the side chain. The significance of the ligands is that by placing a ligating side chain on a ring carbon (C-3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton are available for hydrogen bonding. As desired, seven chelate complexes examined by X-ray diffraction all showed intramolecular hydrogen bonding between the pyrazole N-H and a chloride ligand in the cis position. In addition, however, intermolecular hydrogen bonding could be controlled by the substituent at C-5: complexes with either a methyl at C-5 or no substituent there showed significant intermolecular hydrogen bonding interactions, which were completely avoided by placing a tert-butyl group at C-5. The acidity of two complexes in acetonitrile solutions was estimated to be closer to that of pyridinium ion than those of imidazolium or triethylammonium ions.     

A DFT study of model complexes of zinc hydrolases and their inhibition by hydroxamic acids

DFT calculations carried out on zinc acetate and zinc hydroxamates using the Hartree-Fock and B3LYP methods with the 6-311+G basis set give a series of stable pseudotetrahedral chelates (ZnL(2)) (L = OAc, FA, AA, NMeAA, GA, SA). Addition of a water molecule to these chelates gives the hydrates, ZnL(2).H(2)O, which in all cases are energetically more stable than the corresponding chelate. Hydrates formed from O,O coordinated hydroxamate species with a five-membered chelate ring contain water molecules occupying vacant coordination sites of the zinc atom. In contrast, those formed from zinc chelates with four-membered chelate rings contain a water molecule inserted into the chelate ring to give a six-membered ring in which one hydrogen of the water molecule is H-bonded to an oxygen atom of the zinc chelate with the water oxygen strongly bonded to the zinc. A slight lengthening of the H-bonded O-H bond suggests incipient hydroxide activation of water by zinc. In contrast, the O,O bonded hydroxamates do not incorporate water into the chelate ring nor activate the water in accordance with the ability of hydroxamic acids to inhibit zinc containing metalloenzymes.     

Crystal Structures of DOTMA Chelates from Ce3+ to Yb3+: Evidence for a Continuum of Metal Ion Hydration States

The crystal structures of chelates formed between each stable paramagnetic lanthanide ion and the octadentate polyamino carboxylate ligand DOTMA are described. A total of 23 individual chelates structures were obtained; in each chelate the coordination geometry around the metal ion is best described as a twisted square antiprism (torsion angle −25.0°–−31.4°). Despite the uniformity of the general coordination geometry provided by the DOTMA ligand, there is a considerable variation in the hydration state of each chelate. The early Ln³⁺ chelates are associated with a single inner sphere water molecule; the Ln-OH₂ interaction is remarkable for being very long. After a clear break at gadolinium, the number of chelates in the unit cell that have a water molecule interacting with the Ln³⁺ decreases linearly until at Tm³⁺ no water is found to interact with the metal ion. The Ln-OH₂ distance observed in the chelates of the later Ln³⁺ ions are also extremely long and increase as the ions contract (2.550–2.732 Å). No clear break between hydrated and dehydrated chelates is observed; rather this series of chelates appear to represent a continuum of hydration states in which the ligand gradually closes around the metal ion as its ionic radius decreases (with decreased hydration) and the metal drops down into the coordination cage.     

Density-functional theory structures of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complexes for ions across the lanthanide series

The use of organically chelated lanthanides in diagnosis and treatment is a rapidly growing field in medicine. In order to gain a deeper understanding into the properties of these chelates, particularly spectroscopic, density-functional calculations have been performed on a series of lanthanide ions chelated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. Based on the results of these calculations, it has been concluded that the local symmetry experienced by the chelated lanthanide ion may be treated as being axial, which will make the interpretation of their spectroscopic properties greatly simplified. It has also been suggested that the so-called "capping" water molecule at the ninth coordination position of the lanthanide is hydrogen bonded to the acetate oxygens of the sidearms, rather than coordinated as the ninth ligand of the lanthanide.     

配合物3AgNO3·2[C3H7S(CH2)2SC3H7]的晶体结构

本文测定了配合物3AgNO3·2BPrTE的晶体结构, 该晶体属三斜晶系, 空间各为PI,晶胞参数: a=0.8945(1), b=1.2355(2), c=1.3572(5)nm; α=98.69(2)°, β=92.74(2)°, γ=90.45(1)°; V=1.480nm^3; Z=2, 分子中三个Ag原子的配位数均为5, 但它们的配位多面体各不相同, Ag(3)为四方锥体, Ag(2)为三角双锥, Ag(1)则介于两者之间, NO3^-以单齿、不等长双齿和等长双齿两种形式配位于Ag原子。配体BPrTE也具有两种构象, 反式构象具有C1对称性, 并以两种形式和Ag原子配位, 偏转式构象不具有C4对称性, 与Ag原子形成五元螯合环, 分子为三维无限长链结构。     

Molecular design of new magnetically active copper complexes with heteroaromatic schiff bases and azo compounds

Copper chelates with tridentate ligands containing pyridine or pyrazole ring at the azomethine or azo fragment were synthesized by chemical electrochemical methods, and their structure was characterized by the EXAFS spectra. Thermal magnetochemical analysis of the complexes revealed antiferromagnetic exchange interaction in all complexes. The exchange interaction parameter of the complex containing an N-tosylamino group in the ortho position with respect to the azomethine group is much lesser than that of the corresponding complex having an oxygen atom in the same position. The copper chelate derived from azopyrazole ligand shows low-temperature ferromagnetic phase transition.     

Mass spectra of SnI2

The thermal and spectral properties of the chelates of quinizarin with copper, cobalt and nickel have been investigated. The decreasing order of thermal stability for the chelates is Ni > Co > Cu. The chelates are compared with the corresponding chelates of naphthazarin. The effect on the thermal stability of the addition of a benzene ring to naphthazarin is compared with a previous study on 2,4-dinitrosoresorcinol and 2,4-dinitroso-1,3-naphthalenediol. Several unsuccessful attempts were made to prepare a zinc chelate of this ligand.     

Adduct formation of copper(II) chelates of 1-hydroxypyrazole 2-oxides with substituted pyridines

Equilibrium constants have been determined for the adduct formation of 10 copper(II) chelates of the derivatives of 1-hydroxypyrazole 2-oxide with nine substituted pyridines at room temperature in chloroform solution. These adducts were shown to have 1:1 stoichiometry. All the stabilities of the adducts were governed by: (1) σ-donating ability of the nitrogen atom in the substituted pyridines to the copper(II) chelates, (2) electron-attracting forces of substituents at the 3- and 4-positions of the phenyl ring in the chelate ligands, and (3) the magnitude of the polar substituent constant of the substituents in the pyrazole ring of the chelate ligands.     

Crystal structures of two complexes of the rare-earth-DOTA-binding antibody 2D12.5: ligand generality from a chiral system

We report the crystal structures of antibody 2D12.5 Fab bound to an yttrium-DOTA analogue and separately to a gadolinium-DOTA analogue. The rare earth elements have many useful properties as probes, and 2D12.5 binds the DOTA (1,4,7,10-tetraazacyclododecane-N,N',N' ',N' "-tetraacetic acid) complexes of all of them (Corneillie et al. J. Am. Chem. Soc. 2003, 125, 3436-3437). The structures show that there are no direct protein-metal interactions: a bridging water acts as a link between the protein and metal, with the chelate present as the M isomer in each case. DOTA forms an amphipathic cylinder with the charged carboxylate groups toward the face of the chelate near the metal ion, while nonpolar methylene groups from the macrocycle and the carboxymethyl groups occupy the rear and sides of the molecule. The orientation of the metal-DOTA in the 2D12.5 complex places most of the methylene carbon atoms of DOTA in hydrophobic contact with aromatic protein side chains. Other binding interactions between the metal complex and the antibody include a bidentate salt bridge, four direct H-bonds, and four to five water-mediated H-bonds. We find that 2D12.5 exhibits enantiomeric binding generality, binding yttrium chelates in both Lambda(deltadeltadeltadelta) and Delta(lambdalambdalambdalambda) configurations with modestly different affinities. This develops from the symmetrical nature of the DOTA chelate, which places heteroatoms and hydrophobic atoms in approximately the same relative positions regardless of the helicity of DOTA.