Lanthanide(III) complexes that contain a self-immolative arm: potential enzyme responsive contrast agents for magnetic resonance imaging

Enzyme-responsive MRI-contrast agents containing a "self-immolative" benzylcarbamate moiety that links the MRI-reporter lanthanide complex to a specific enzyme substrate have been developed. The enzymatic cleavage initiates an electronic cascade reaction that leads to a structural change in the Ln(III) complex, with a concomitant response in its MRI-contrast-enhancing properties. We synthesized and investigated a series of Gd(3+) and Yb(3+) complexes, including those bearing a self-immolative arm and a sugar unit as selective substrates for β-galactosidase; we synthesized complex LnL(1), its NH(2) amine derivatives formed after enzymatic cleavage, LnL(2), and two model compounds, LnL(3) and LnL(4). All of the Gd(3+) complexes synthesized have a single inner-sphere water molecule. The relaxivity change upon enzymatic cleavage is limited (3.68 vs. 3.15 mM(-1) s(-1) for complexes GdL(1) and GdL(2), respectively; 37 °C, 60 MHz), which prevents application of this system as an enzyme-responsive T(1) relaxation agent. Variable-temperature (17)O NMR spectroscopy and (1)H NMRD (nuclear magnetic relaxation dispersion) analysis were used to assess the parameters that determine proton relaxivity for the Gd(3+) complexes, including the water-exchange rate (k(ex)(298), varies in the range 1.5-3.9×10(6) s(-1)). Following the enzymatic reaction, the chelates contain an exocyclic amine that is not protonated at physiological pH, as deduced from pH-potentiometric measurements (log K(H)=5.12(±0.01) and 5.99(±0.01) for GdL(2) and GdL(3), respectively). The Yb(3+) analogues show a PARACEST effect after enzymatic cleavage that can be exploited for the specific detection of enzymatic activity. The proton-exchange rates were determined at various pH values for the amine derivatives by using the dependency of the CEST effect on concentration, saturation time, and saturation power. A concentration-independent analysis of the saturation-power-dependency data was also applied. All these different methods showed that the exchange rate of the amine protons of the Yb(III) complexes decreases with increasing pH value (for YbL(3), k(ex)=1300 s(-1) at pH 8.4 vs. 6000 s(-1) at pH 6.4), thereby resulting in a diminution of the observed CEST effect.     

Synthesis of Lanthanide Coordination Polymers with Benzophenone-4,4-dicarboxylate: Effect of Lanthanide Contraction on Structures

Introduction Recently, the coordination polymers based on dicar-boxylic acid have been studied extensively for their importance as promising materials.1-7 So the rational design and synthesis of novel coordination polymers with useful functions attract considerable attention. As well known, the design of extended structure with po-tential applications can be realized by starting with connecting ligands capable of binding metal centers strongly and predictably to afford the structures with expe…     

Lanthanide Complexes of Azidophenacyl‐DO3A as New Synthons for Click Chemistry and the Synthesis of Heterometallic Lanthanide Arrays

Lanthanide complexes of azidophenacyl DO3A are effective substrates for click reactions with ethyne derivatives, giving rise to aryl triazole appended lanthanide complexes, in which the aryl triazole acts as an effective sensitising chromophore for lanthanide luminescence. They also undergo click chemistry with propargylDO3A derivatives, giving rise to heterometallic complexes.     

钆离子:周期表中最高自旋的离子

钆离子是元素周期表中自旋值最大的离子,其轨道角动量被完全淬灭,具有十分特殊的电子结构。本文以核磁共振造影剂以及分子自旋量子比特为例介绍了钆离子在前沿科技中的应用。     

Lanthanide-Based Probes for Imaging Detection of Enzyme Activities by NIR Luminescence,T1- and ParaCEST MRI

Applying a single molecular probe to monitor enzymatic activities in multiple, complementary imaging modalities is highly desirable to ascertain detection and to avoid the complexity associated with the use of agents of different chemical entities. We demonstrate here the versatility of lanthanide (Ln³⁺) complexes with respect to their optical and magnetic properties and their potential for enzymatic detection in NIR luminescence, CEST and T1 MR imaging, controlled by the nature of the Ln³⁺ ion, while using a unique chelator. Based on X-ray structural, photophysical, and solution NMR investigations of a family of Ln³⁺ DO3A-pyridine model complexes, we could rationalize the luminescence (Eu³⁺, Yb³⁺), CEST (Yb³⁺) and relaxation (Gd³⁺) properties and their variations between carbamate and amine derivatives. This allowed the design of $$ probes which undergo enzyme-mediated changes detectable in NIR luminescence, CEST and T1-weighted MRI, respectively governed by variations in their absorption energy, in their exchanging proton pool and in their size, thus relaxation efficacy. We demonstrate that these properties can be exploited for the visualization of β-galactosidase activity in phantom samples by different imaging modalities: NIR optical imaging, CEST and T1-weighted MRI.     

二乙三胺五乙酸吡哆醇酯配体及其钆配合物的合成、弛豫率和肝靶向性研究

由维生素B₆族化合物吡哆醇及其衍生物与二乙三胺五乙酸(DTPA)双酸酐反应合成了一系列二乙三胺五乙酸吡哆醇酯配体.将这些配体与GdCl₃·6H₂O反应后得到了钆配合物.测定了这些配合物在水溶液中水质子的纵向弛豫率R₁.与母体配合物GdDTPA相比,R₁值略有提高.配体用放射性核素⁹⁹Tc标记,研究了其肝靶向性.结果表明,配体2和6的肝靶向性较为明显.动物核磁共振成像实验进一步证实由这两种配体合成的钆配合物对大鼠肝部的造影信号明显增强     

Peptide synthesis catalysed by papain immobilised on polymer supports: Effect of the macromolecular structure and reaction conditions on synthesis

Papain immobilised on different types of polymeric supports was used for the synthesis of peptides in aqueous-organic solvent mixtures. The effects of the nature of the polymer support, degree of crosslinking, nature and length of the spacer grouping between the polymer backbone and the point of attachment of the enzyme, and reaction conditions like pH, concentration of nucleophile and the immobilised enzyme content on the course of the synthesis were investigated. Divinylbenzene-crosslinked polystyrene, divinylbenzenecrosslinked polyacrylamide and N,N′-methylene-bis-acrylamide-crosslinked polyacrylamide systems immobilised with papain were used for these studies. An increase in the length of the spacer arm and an increase in hydrophilicity invariably resulted in an increase in the yield of the peptide synthesis. Papain immobilised on polystyrene-PEG supports and tetraethyleneglycol-crosslinked polystyrene supports was determined to be more efficient in effecting peptide synthesis when compared to other polystyrene-based supports.     

Towards an Improved Design of MRI Contrast Agents: Synthesis and Relaxometric Characterisation of Gd-HPDO3A Analogues

The properties of Ln^III-HPDO3A complexes as relaxation enhancers and paraCEST agents are essentially related to the hydroxylpropyl moiety. A series of three HPDO3A derivatives, with small modifications to the hydroxyl arm, were herein investigated to understand how heightened control can be gained over the parameters involved in the design of these agents. A full ¹H and ¹⁷O-NMR relaxometric analysis was conducted and demonstrated that increasing the length of the OH group from the lanthanide centre significantly enhanced the water exchange rate of the gadolinium complex, but with a subsequent reduction in kinetic stability. Alternatively, the introduction of an additional methyl group, which increased the steric bulk around the OH moiety, resulted in the formation of almost exclusively the TSAP isomer (95 %) as identified by ¹H-NMR of the europium complex. The gadolinium analogue of this complex also exhibited a very fast water exchange rate, but with no detectable loss of kinetic stability. This complex therefore demonstrates a notable improvement over Gd-HPDO3A.     

1D Lanthanide Coordination Polymers Based on 3-（Pyridin-4,yl）benzoic Acid： Syntheses, Structures and Luminescent Properties

Four novel 1D lanthanide coordination polymers with formula [Ln(3,4-pybz)3(H2O)2· H2O]n (Ln = 1 Sm; 2 Eu; 3 Tb; 4 Dy, 3,4-Hpybz = 3-(pyridin-4-yl)benzoic acid) have been synthesized by hydrothermal reactions of lanthanide oxide and 3-(pyridine-4-yl) benzoic acid. Single-crystal X-ray diffraction shows that the four compounds are isostructural. They all crystallize in a monoclinic system, space group P1. They have a doubly carboxylate-bridged infinite-chain structure with alternating Ln-(carboxylate)2-Ln linkages and one chelating carboxylate group on each metal center. The Ln ion also combines to two water molecules to form an eight-coordinate square antiprismatic geometry. The pyridine nitrogen atoms of the ligand do not coordinate to the metal centers but direct the formation of a 3D network through hydrogen bonding with coordinated water molecules. The photoluminescent properties of 2 and 3 have been also studied.     

Selective Anchoring of GdIII Chelates on the External Surface of Organo‐Modified Mesoporous Silica Nanoparticles: A New Chemical Strategy To Enhance Relaxivity

The optimization of the physico‐chemical properties of both Gd^III chelates and nanocarriers is of great importance for the development of effective nanosystems for magnetic resonance imaging (MRI) applications. With this aim, macrocyclic Gd^III chelates were selectively attached to the pendant amino groups exposed to the external surface of spheroidal mesoporous silica nanoparticles (MSNs). This was achieved by treating the metal complexes with MSNs that contained the templating surfactant molecules confined within the silica channels (hexadecyltrimethylammonium (CTA)/MSN), followed by extraction of the surfactant. The nanoparticles showed greatly improved ¹H relaxometric efficiency relative to corresponding systems that also feature Gd^III chelates conjugated inside the pores. A further significant relaxivity enhancement was observed after chemical transformation of the free amino groups into amides. The ionic relaxivity of the final nanoparticles (r_1p=79.1 mM ^?1 s^?1; 0.5 T, 310 K) is one of the highest reported so far.     

稀土离子(La3+, Gd3+, Yb3+, Ce3+)对线粒体的氧化损伤

主要考察了稀土离子对线粒体氧化损伤(膜脂质过氧化、膜蛋白氧化、线粒体DNA氧化)的作用。结果表明,稀土离子(La3 ,Gd3 ,Yb3 ,Ce3 )浓度大于2×10-5mol.L-1时,对线粒体膜脂质过氧化、膜蛋白氧化均有明显的促进作用;在对Fe2 诱导的线粒体氧化过程中,La3 ,Gd3 和Yb3 能明显地增强Fe2 的氧化作用,而Ce3 对Fe2 的作用表现出明显的拮抗作用,此外Ce3 对Fe2 诱导的线粒体DNA氧化损伤表现出明显的拮抗作用,显示了Ce3 的特殊性。     

Lanthanide(III) complexes of a mono(methylphosphonate) analogue of H4dota: the influence of protonation of the phosphonate moiety on the TSAP/SAP isomer ratio and the water exchange rate

A monophosphonate analogue of H4dota, 1,4,7,10-tetraazacyclododecane-4,7,10-tris(carboxymethyl)-1-methylphosphonic acid (H5do3aP), and its complexes with lanthanides were synthesized. Multinuclear NMR studies reveal that, in aqueous solution, lanthanide(III) complexes of the ligand exhibit structures analogous to those of H4dota complexes. Thus, the central ion is nine-coordinate, surrounded by four nitrogen atoms, three acetate and one phosphonate oxygen atoms, and one water molecule in an apical position. For complexes of H5do3aP with Ln(III) ions in the middle of the series, the abundance of the desired twisted square-antiprismatic (TSAP) isomer is higher than for the corresponding H4dota complexes. The TSAP/square-antiprismatic (SAP) isomer ratio is highly sensitive to protonation of the phosphonate group: a higher abundance of the TSAP isomer was found in acidic solutions. The microscopic protonation constants of the TSAP isomers are higher than those of the SAP isomers. The presence of one water molecule in the first coordination sphere of the complexes in the pH region studied (pH 2.5-7.0) is confirmed by 17O NMR spectroscopy. The results of a simultaneous fit of variable-temperature 17O NMR relaxation data and 1H NMRD profiles show that the residence time of water (tauM) in the Gd(III) complex is much smaller than for [Gd(dota)(H2O)]-. The exchange rate appears to be dependent on the pH of the solution. The values of tauM are 37, 40, and 14 ns at pH 2.5, 4.7, and 7.0, respectively. These observations can be explained by an extensive second-sphere hydrogen-bonding network that varies with the state of protonation of the phosphonate moiety. Upon protonation of the complex, the second-sphere hydration probably becomes more ordered, which may result in a decrease in penetrability and an increase in tauM. The relaxivity of the Gd(III) complex is almost independent of the pH and is equal to 4.7 s(-1) mM(-1) (20 MHz, pH 7 and 37 degrees C). The solid-state structure was determined for the Nd(III) complex. It crystallizes as the TSAP isomer and the unit cell contains two independent molecules of the complex with different Nd-O(water) bond lengths of 2.499 and 2.591 A.     

Lanthanide(III) Complexes of 4,10‐Bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H6do2a2p) in Solution and in the Solid State: Structural Studies Along the Series

Complexes of 4,10‐bis(phosphonomethyl)‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid (trans‐H₆do2a2p, H₆ L ) with transition metal and lanthanide(III) ions were investigated. The stability constant values of the divalent and trivalent metal‐ion complexes are between the corresponding values of H₄dota and H₈dotp complexes, as a consequence of the ligand basicity. The solid‐state structures of the ligand and of nine lanthanide(III) complexes were determined by X‐ray diffraction. All the complexes are present as twisted‐square‐antiprismatic isomers and their structures can be divided into two series. The first one involves nona‐coordinated complexes of the large lanthanide(III) ions (Ce, Nd, Sm) with a coordinated water molecule. In the series of Sm, Eu, Tb, Dy, Er, Yb, the complexes are octa‐coordinated only by the ligand donor atoms and their coordination cages are more irregular. The formation kinetics and the acid‐assisted dissociation of several Ln^III–H₆ L complexes were investigated at different temperatures and compared with analogous data for complexes of other dota‐like ligands. The [Ce( L )(H₂O)]^3? complex is the most kinetically inert among complexes of the investigated lanthanide(III) ions (Ce, Eu, Gd, Yb). Among mixed phosphonate–acetate dota analogues, kinetic inertness of the cerium(III) complexes is increased with a higher number of phosphonate arms in the ligand, whereas the opposite is true for europium(III) complexes. According to the ¹H NMR spectroscopic pseudo‐contact shifts for the Ce–Eu and Tb–Yb series, the solution structures of the complexes reflect the structures of the [Ce(H L )(H₂O)]^2? and [Yb(H L )]^2? anions, respectively, found in the solid state. However, these solution NMR spectroscopic studies showed that there is no unambiguous relation between ³¹P/¹H lanthanide‐induced shift (LIS) values and coordination of water in the complexes; the values rather express a relative position of the central ions between the N₄ and O₄ planes.     

Self-Assembly of 1D Double-Chain and 3D Diamondoid Networks of Lanthanide Coordination Polymers through In Situ-Generated Ligands: High-Pressure CO2 Adsorption and Photoluminescence Properties

Two new lanthanide-based coordination polymers, [Sm₂(bzz)(ben)₆(H₂O)₃]·0.5H₂O (1) and [Eu(bbz)(ben)₃] (2), were synthesized and characterized. The described products were formed from in situ-generated benzoate (ben) and N’-benzoylbenzohydrazide (bbz) ligands, which were the products of transformation of originally added benzhydrazide (bzz) under hydrothermal conditions. Compound 1 exhibits a one-dimensional (1D) double-chain structure built up from the connection of the central Sm³⁺ ions with a mixture of bzz and ben ligands. On the other hand, 2 features a 3D network with a 4-connected (6⁶) dia topology constructed from dinuclear [Eu₂(ben)₆] secondary building units and bbz linkers. High-pressure CO₂ sorption studies of activated 1 show that maximum uptake increases to exceptionally high values of 376.7 cm³ g⁻¹ (42.5 wt%) under a pressure of 50 bar at 298 K with good recyclability. Meanwhile, 2 shows a typical red emission in the solid state at room temperature with the decay lifetime of 1.2 ms.     

NMR Characterization of Lanthanide(3+) Complexes of Tetraazatetrakisphosphinato and Tetraazatetra­kisphosphonato Ligands

The three‐dimensional structures in aqueous solution of the entire series of the Ln³⁺ complexes [Ln(DOTP*‐Et)]^? (formed from the free ligand P,P′,P″,P′′′‐[1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrayltetrakis(methylene)]tetrakis[P‐ethylphosphinic acid] (H₄DOTP*‐Et) were studied by NMR techniques to rationalize the parameters governing the relaxivity of the Gd³⁺ complex and evaluate its potential as MRI contrast agent. From the ¹H‐ and ³¹P‐NMR lanthanide‐induced‐shift (LIS) values, especially of the [Yb(DOTP*‐Et)]^? complex, it was concluded that the [Ln(DOTP*‐Et)]^? complexes adopt in solution twisted square antiprismatic coordination geometries which change gradually their coordination‐cage structure along the lanthanide series. These complexes have no inner‐sphere‐H₂O coordination, and preferentially have the (R,R,R,R) configuration of the P‐atoms in the pendant arms. Self‐association was observed in aqueous solution for the tetraazatetrakisphosphonic acid ester complexes [Ln(DOTP*‐OEt)]^? (=[Ln(DOTP‐Et)]^?) and [Ln(DOTP*‐OBu)]^? (=[Ln(DOTP‐Bu)]^?) at and above 5 mM concentration, through analysis of ³¹P‐NMR, EPR, vapor‐pressure‐osmometry, and luminescence‐spectroscopic data. The presence of the cationic detergent cetylpyridinium chloride (CPC; but not of neutral surfactants) shifts the isomer equilibrium of [Eu(DOTP*‐OBu)]^? to the (S,S,S,S) form which selectively binds to the cationic micelle surface.     

Synthesis of Two Schiff Base Transition Metal Complexes Bearing Morpholine Side Chains and Kinetics of PNPP Catalytic Hydrolysis in Brij35 Micelle

Two Schiff base transitional metal complexes bearing morpholine side chains were synthesized and characterized, and were used as a simulative hydrolase in the catalytic hydrolysis of p‐nitrophenyl picolinate (PNPP) in this article. A mechanism of PNPP catalytic hydrolysis in the Brij35 micellar solution was proposed and supported by the results of the spectral analysis and the kinetic calculation. The kinetic model of PNPP catalytic hydrolysis was studied. The some kinetic and the thermodynamic constants on the catalytic reaction were calculated. The results of the study show that the metallomicelle made up of the Schiff base transitional metal complexes and Brij35 micelle revealed a good catalytic activity in PNPP catalytic hydrolysis; the rate of the PNPP catalytic hydrolysis is increased following the increase of the pH values in the buffer solution and affected by the polarization action of metal ion of complex.     

The Long and Bright Path of a Lanthanide MOF: From Basics towards the Application

The development of portable, reliable, and low-cost sensors for assessing the quality of natural water sources is of high relevance in developing countries as they can serve as an intermediate solution prior to the building of permanent potable water distribution infrastructure. These sensors should be simple to operate by non-trained operators and easy to manufacture locally. Lanthanide-based metal–organic frameworks (MOFs) offer a trustable platform due to their intense emission in regions of the visible spectra and their high sensitivity to fluorides in water. Cotton was chosen as a substrate due to its high hydrophilicity which, together with the highly porous nature of the MOF, allows for shorter reaction times. The modified cotton was characterized by XRD, SEM as well as XAFS, hence probing the presence of [Tb(BTC)₆(H₂O)] (Tb-BTC) attachment to cotton. Changes in the emission when Tb-BTC modified cotton was exposed to water and aqueous fluoride solutions were monitored as a function of time. Crystalline phase changes were identified that correlated to structural information. Finally, the Tb-BTC modified cotton was used to build a fluoride demonstrator sensor with a linear response of up to 10 mg L⁻¹ and a limit of detection of 0.8 mg L⁻¹, making it suitable for drinking water analysis under international regulations.     

Novel Single- and Double-Layer and Three-Dimensional Structures of Rare-Earth Metal Coordination Polymers: The Effect of Lanthanide Contraction and Acidity Control in Crystal Structure Formation

Lanthanide atom sizes (the lanthanide contraction) directly control the type of structure formed by the coordination of a single multidentate ligand, 3,5-pyrazoledicarboxylic acid (H(3)pdc). Single-layer, double-layer ([Eu(2)(Hpdc)(3)(H(2)O)(6)], see picture), and three-dimensional networks were found. Control of the reaction pH plays a key role in the structure formation in this system.