Chantal Galaup

Mono(di)nuclear Europium(III) Complexes of Macrobi(tri)cyclic Cryptands Derived from Diazatetralactams as Luminophores in Aqueous Solution

To increase the excellent light-emitting properties of the Eu3+ ion, macrobicyclic and macrotricyclic ligands 7 – 10, incorporating a 18-membered tetralactam ring (acting as a lanthanide binding site) and a sensitizer group (2,2′-bipyridine or 2,2′-bipyridine 1,1′-dioxide moiety), were synthesized. The mononuclear and dinuclear europium cryptates derived from these ligands were isolated and characterized. Their luminescent properties and those of the corresponding cryptates containing a phenanthroline group (see 11 and 12) were examined in H2O and D2O solutions at 77 and 300 K. It results that the tetralactam moiety plays a major role in the efficient shielding of the complexed Eu3+ ion from the water environment. The cryptands incorporating the bipyridine unit are the most promising labels according to their photophysical properties (excitation maxima, emission decay lifetime, relative luminescent yield). In contrast with literature data, introduction of N-oxide groups in the bipyridine chromophore weakens the luminescence properties of the cryptate.

Novel terpyridine macrocyclic complexing agent and luminescence of its neutral Ln(III) complexes (Ln=Eu, Tb, Sm, Dy) in aqueous solution

Abstract A very convenient synthesis of an 18-membered triaza-macrocyclic ligand bearing one endocyclic terpyridine unit and three acetate pendant groups is reported. This nonadentate ligand forms very stable neutral lanthanide complexes in aqueous solution and efficiently shields the metal ion from the water environment. In this medium the Eu(III) and Tb(III) complexes are strongly fluorescent through an energy-transfer luminescence pathway (τ∼1 ms and Φ∼20%).

A click procedure with heterogeneous copper to tether technetium-99m chelating agents and rhenium complexes. Evaluation of the chelating properties and biodistribution of the new radiolabelled glucose conjugates.

An efficient protocol was developed to tether chelating agents and rhenium complexes onto a glucoside scaffold with a heterogeneous copper catalyst via click chemistry. The supported catalyst avoids the formation of unwanted copper complexes during the cyclisation step. The possibility to graft a pre-chelated M(CO)(3) core by click chemistry onto a biomolecule was highlighted for the first time. (99m)Tc(CO)(3)-glucoconjugates displayed excellent in vitro stability, a fast in vivo blood clearance and a low specific organ uptake or long-term retention in spleen and stomach.

New Macrobicycles Containing a Tetralactam Moiety: Template Synthesis and Study of their Binding with Lanthanides

Abstract The synthesis of macrobicyclic cryptands 1 , 2 from an 18-membered diazatetralactam and 6,6′-bis(bromomethyl)-2,2′-bipyridine or 2,6-bis(3-bromomethyl-1-pyrazolyl)pyridine has been investigated using various metal carbonates. The analysis of the distribution products by gel permeation chromatography showed that macrocyclization process was markedly conditioned by cation template effects. Optimum yields were obtained for Li + and Na + in the preparation of 1 and 2 , respectively. The cryptate structure of the corresponding complexes of Ln(III) (Ln=Eu, Tb, Gd) is discussed on the basis of spectroscopic and photophysical data.

Time‐Resolved Luminescence in Aqueous Solution − New Europium Labels Derived from Macro(bi)cyclic Ligands with Aminocarboxylic Units

A new family of macro(bi)cyclic ligands has been designed and synthesized, with the goal of developing lanthanide labels suitable for time-resolved luminescence-based biological applications. They are constructed from diamide (3) or tetralactam (4) complexing moieties associated with an intracyclic 2,2′-bipyridine chromophore and two exocyclic carboxylic groups. The luminescence properties of their Eu3+ complexes were studied in aqueous solution. In this medium, noticeable enhancements in the lifetime and quantum yield were observed, in comparison with those of other bipyridine-based ligands considered interesting as luminescent labels. The effects of coordinated water molecules, LMCT states, and ligand triplet state energy on the nonradiative deactivation processes to the ground state were examined. According to these results and in view of the stability of these complexes in aqueous solutions, the [Eu(3)]+ complex may be considered as a promising luminescent bioprobe.

Luminescence of Eu3+ and Tb3+ Complexes of Two Macrobicyclic Ligands Derived from a Tetralactam Ring and a Chromophoric Antenna

Two macrobicyclic ligands derived from an 18-membered tetralactam ring and 2,2′-bipyridine or 2,6-bis(pyrazol-1-yl)pyridine moieties, 1 and 2, respectively, form stable complexes with GdIII, EuIII, and TbIII ions in aqueous solution. The ligand-based luminescence is retained in the GdIII cryptates, whereas this radiative deactivation is quenched in the EuIII and TbIII cryptates by ligand-to-metal energy transfer, resulting in the usual metal-centered emission spectra. Singlet- and triplet-state energies, emission-decay lifetimes, and luminescence yields were measured. [Tb⊂1]3+ cryptate shows a long luminescence lifetime (τ=1.12 ms) and a very high metal luminescence quantum yield (Φ=0.25) in comparison with those reported in the literature for Tb3+ complexes sensitized by a bipyridine chromophore. By comparison to [Ln⊂1]3+, [Ln⊂2]3+ presents markedly lower luminescence properties, due to worse interaction between the 2,6-bis(pyrazol-1-yl)pyridine unit and the metal ion. Moreover, the luminescent metal and the triplet ligand energy levels of [Eu⊂2]3+ do not match. The effects of H2O molecules coordinated to the metal centre and of thermally activated decay processes on nonradiative deactivation to the ground-state are also reported.

Eu(III) complex of a macrocyclic ligand derived from 2,2′-bipyridine and iminodiacetic acid: Synthesis, luminescence and phosphate diester transesterification properties

Abstract A very convenient synthesis of a macrocyclic ligand bearing two endocyclic amide and two exocyclic carboxylate groups (lanthanide binding sites) and one sensitizer (2,2′-biphridine unit) is described. It is shown that the corresponding Eu(III) complex bearing a single positive charge and incorporating two water molecules in the first coordination sphere of the metal ion is strongly fluorescent on the basis of energy-transfer luminescence (Φ = 0.36 in D 2 O solution at 300 K) and cleaves a RNA model phosphate diester in aqueous solution.

A biologically relevant ceramide fluorescent probe to assess the binding of potential ligands to the CERT transfer protein

The conversion of ceramide into sphingomyelin (SM) was only recently considered in relation to cancer. Overexpression of the CERT protein, responsible for a highly specific inter-organelle ceramide transfer step along the de novo SM synthesis pathway, has been associated with multi-drug resistance of cancer cells. Identification of new CERT antagonists may therefore lead to potential resensitizing agents. This work describes the first attempt to design a ceramide-based fluorescent probe optimised to evaluate the binding of potential CERT ligands. A prototypical structure with an ω-labelled sphingosine backbone was selected. Its possible recognition mode by CERT was first evaluated by means of a precursory molecular modelling study. Three derivatives with various amide chain lengths were prepared and tested. The binding efficiency was shown to be proportional to the lipophilicity of the acyl moiety. The best compound bearing a C16 amide fragment was used to implement a practical binding experiment. Facile assessment of the recognition by the CERT START domain of various structures was thus ensured. Metabolism and imaging experiments were also used to illustrate the capacity of the proposed fluorescent ceramide analogue to mimic the natural ceramide cellular behaviour. This work led to the synthesis and evaluation as an efficient CERT START domain ligand of a ω-biotinylated ceramide, a potential probe to develop the screening of new CERT antagonists.

Synthesis and structure of macrocyclic dioxa-, dithia-, diazatetralactams and derivatives

Abstract The high yield stepwise synthesis of 18-membered dioxa-, dithia- and diazatetralactams is described. The two key steps are: i) the dissymetrization of the reactivity of a diacid via its cyclic anhydride and ii) the activation-cyclization of the intermediate diamide diacid avoiding the high-dilution technique. Two series of diazatetralactam derivatives are prepared: bibranched compounds bearing various substituents and macrobicyclic or macrotricyclic species with phenantroline units. The main conformer of the dioxatetralactam was found by 13C nmr and molecular modelling to have a D2 symmetry while the dithiatetralactam in vacuo and the Boc substituted diazatetralactam in the solid state have a C2 symmetry.

Bifunctional Gd(III) and Tb(III) chelates based on a pyridine-bis(iminodiacetate) platform, suitable optical probes and contrast agents for magnetic resonance imaging.

To study the physicochemical properties of lanthanide complexes derived from a bifunctional chelating agent based on a PMN-tetraacetic acid moiety {PMN-tetraacetic acid (1): [2,6-pyridinediylbis(methylene nitrilo)-tetraacetic acid]}, 4-carboxylic acid substituted pyridine derivative (2) was synthesized. This ligand forms heptadentate (N3 O4 ) Ln(III) complexes (Ln = Gd, Eu, Tb), with two water molecules completing the inner coordination sphere of the metal. The parameters that govern the relaxivity of the Gd(III) complex and the luminescence of Eu(III) and Tb(III) complexes were obtained by (17) O and (1) H NMR studies and time-resolved fluorescence experiments, respectively. The gadolinium and terbium complexes show interesting properties either for MRI or FOR optical imaging; that is, for the Gd complex, a high proton relaxivity (r1  = 6.4 s(-1) mM(-1) at 20 MHz) with short water residence time (τM  = 38.5 ns); for the Tb complex, a luminescence lifetime of 1.22 ms at room temperature and a luminescence quantum yield of 10%. The kinetic stability of these complexes toward blood protein, cation or bioactive oxyanion was also examined. The Gd(2)(H2O)2 complex does not interact with human serum albumin, but undergoes a transmetalation reaction with Zn(II) in a phosphate buffer solution (pH 7.4), rather similar to that of Gd-DTPA-BMA(H2 O). On the other hand, as observed for Eu and Tb complexes, these chelates do not form ternary complexes with bidentate anions such as l-lactate, citrate or carbonate. Finally, a phosphatidylserine-specific hexapeptide (TLVSSL) was grafted on Gd or Tb chelates, and the Gd-peptide conjugate was used in vitro for targeting apoptotic cells.