Françoise Chuburu

Bis-aminals: efficient tools for bis-macrocycle synthesis

Tetraazamacrocyclic bis-aminals prove to be excellent tools for the synthesis of symmetrical, dissymmetrical or functionalized bis-tetraazamacrocycles. The key feature of the process is the separation of insoluble mono- or bis-quaternary ammonium salts from solution during the course of the alkylation reaction.

A Top‐Down Synthesis Route to Ultrasmall Multifunctional Gd‐Based Silica Nanoparticles for Theranostic Applications

New, ultrasmall nanoparticles with sizes below 5 nm have been obtained. These small rigid platforms (SRP) are composed of a polysiloxane matrix with DOTAGA (1,4,7,10-tetraazacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid)-Gd(3+) chelates on their surface. They have been synthesised by an original top-down process: 1) formation of a gadolinium oxide Gd2O3 core, 2) encapsulation in a polysiloxane shell grafted with DOTAGA ligands, 3) dissolution of the gadolinium oxide core due to chelation of Gd(3+) by DOTAGA ligands and 4) polysiloxane fragmentation. These nanoparticles have been fully characterised using photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), a superconducting quantum interference device (SQUID) and electron paramagnetic resonance (EPR) to demonstrate the dissolution of the oxide core and by inductively coupled plasma mass spectrometry (ICP-MS), mass spectrometry, fluorescence spectroscopy, (29)Si solid-state NMR, (1)H NMR and diffusion ordered spectroscopy (DOSY) to determine the nanoparticle composition. Relaxivity measurements gave a longitudinal relaxivity r1 of 11.9 s(-1)  mM(-1) per Gd at 60 MHz. Finally, potentiometric titrations showed that Gd(3+) is strongly chelated to DOTAGA (complexation constant logβ110 =24.78) and cellular tests confirmed the that nanoconstructs had a very low toxicity. Moreover, SRPs are excreted from the body by renal clearance. Their efficiency as contrast agents for MRI has been proved and they are promising candidates as sensitising agents for image-guided radiotherapy.

Hydrogels incorporating GdDOTA: towards highly efficient dual T1/T2 MRI contrast agents.

Do not tumble dry: Gadolinium-DOTA encapsulated into polysaccharide nanoparticles (GdDOTA NPs) exhibited high relaxivity (r(1) =101.7 s(-1) mM(-1) per Gd(3+) ion at 37 °C and 20 MHz). This high relaxation rate is due to efficient Gd loading, reduced tumbling of the Gd complex, and the hydrogel nature of the nanoparticles. The efficacy of the nanoparticles as a T(1)/T(2) dual-mode contrast agent was studied in C6 cells.

Modification of the Stöber Process by a Polyazamacrocycle Leading to Unusual Core−Shell Silica Nanoparticles

In the view of designing functional nanoparticles, the encapsulation of 1,4,7,10-tetraazacyclododecane (cyclen) within silica nanoparticles using the Stöber process was studied. In the presence of cyclen and tetraethoxysilane (TEOS), silica particles exhibiting an unusual core-shell structure were obtained. On then basis of TEM, DLS, and NMR data, we suggest that the particle core is constituted of hybrid primary nanoparticles resulting from cyclen-silica interactions, whereas the shell formation results from further condensation of unreacted silica precursors. Control experiments performed with the zinc-cyclen complex and ammonia addition suggest that cyclen-TEOS interactions arise from the activation of the silicon alkoxide hydrolysis with the polyazamacrocycle amine groups. These data are discussed in the context of silica biomineralization mechanisms, where polyamine/silica interactions have been shown to play a major role. Moreover, the possibility to control the size and the structure of these nanoparticles makes them promising materials for pharmaceutical applications.

Nickel(II) complexes of cyclen- and cyclam-pyridine: topological reorganisations induced by electron transfer

The NiII complexes of cyclen- and cyclam-pyridine (respectively 1-pyridin-2-ylmethyl-1,4,7,10-tetraazacyclododecane and 1-pyridin-2-ylmethyl-1,4,8,11-tetraazacyclotetradecane denoted [NiIIL1]2+ and [NiIIL2]2+) have been isolated and characterised by X-ray diffraction, UV-visible spectroscopy and electrochemical studies for the [NiIIL2]2+ complex. In particular, the [NiIIL2]2+ complex adopts two distinct and stable geometries (type I and V), which mainly differ by the macrocycle configuration. In solution, the isomerisation process between these two configurations is driven by the nickel-centered electron transfer.

A Convenient Synthetic Route to Polyether-Tagged Cyclam Ligands andTheir Nickel Derivatives

A specific strategy is described for the synthesis of stable polyethylene oxide tagged tetraazamacrocycles (PEO-cyclam) in five steps (overall yields for 12 and 13 48% and 22%, respectively). Various attempts via classical pathways demonstrated: (i) the low reactivity of PEO derivatives, and (ii) the necessity of a stabiliser arm between the cyclam and the PEO chain. Nickel complexes have been prepared and characterised by electrochemistry.

A benzimidazole functionalised DO3A chelator showing pH switchable coordination modes with lanthanide ions

The synthesis of a new macrocyclic chelator incorporating a benzimidazole heterocycle is reported. Lanthanide complexes with macrocyclic chelators based on 1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA) and 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A) are of interest in luminescent, radiopharmaceutical and magnetic resonance (MR) biomedical imaging applications. The benzimidazole DO3A chelator allows for sensitisation of europium(iii), terbium(iii) and ytterbium(iii) luminescence by the heterocycle and also shows a pH dependent coordination change due to protonation of the chelator (pKa = 4.1 for the europium(iii) complex). The thermodynamic stability of the complexes has been investigated by potentiometric titration with the gadolinium(iii) complex showing significantly higher stability than the zinc(ii) complex, where log βZnLH = 28.1 and log βGdLH = 32.1.

Phenylglyoxal for polyamines modification and cyclam synthesis

Abstract The bis-aminals obtained by tetraamine and phenylglyoxal condensation display various behaviours such as equilibrium between different configurations, rearrangements that lead to lactam derivatives, or amine deprotection. Our investigations about them were focused on three different linear amines, and then extended to polyazacycloalkanes cyclen and cyclam. Cyclam was also synthesised with the bis-aminals issued from condensation of linear polyamines with phenylglyoxal. The lactam derivatives described here were moreover, employed for the mono-N-functionalisation of tetraamines by phenyl-acetic acid group.

CYCLENPHOSPHINE SULFIDE : FLUXIONAL BEHAVIOUR AND AMBIDENT REACTIVITY

Abstract The cyclenphosphine sulfide is prepared by reaction of molecular sulfur on cyclenphosphorane, obtained by transaminating hexamethylphosphorous triamide with 1,4,7,10-tetraazacyclododecane (cyclen). The fluxional behaviour of this compound is characterized by NMR 13 C and 31 P spectroscopy. Treatment of the titled compound by n-BuLi, followed by reaction with various electrophiles leads to either N- or S- alkylation according to the nature of the reactant.

Tuning the composition of biocompatible Gd nanohydrogels to achieve hypersensitive dual T1/T2 MRI contrast agents

A series of hydrogel nanoparticles incorporating MRI contrast agents (GdDOTP and MS325) as potential cross-linkers were elaborated by an easy and robust ionotropic gelation process. By this process, high Gd loadings were obtained (between 1.8 and 14.5 × 104 Gd centres per NP). By tuning the cross-linker ionization degree and the nature of the polymer matrix it was possible to boost the r1 relaxivity per Gd centre up to 22-fold. The greatest gains in relaxivity were observed for nanogels for which the polymer matrix was constituted of chitosan and hyaluronan. Relaxivities per Gd centre as high as 100 s-1 mM-1 at 30 MHz can be reached, which highlighted the fact that molecular motion of the Gd chelate was effectively restricted and water access to the inner core of these nanogels was not limited.