Study of Iron Piperazine-Based Chelators as Potential Siderophore Mimetics.

Gram-negative bacteria's resistance such as Pseudomonas aeruginosa and the Burkholderia group to conventional antibiotics leads to therapeutic failure. Use of siderophores as Trojan horses to internalize antibacterial agents or toxic metals within bacteria is a promising strategy to overcome resistance phenomenon. To combat the Pseudomonas sp, we have synthesized and studied two piperazine-based siderophore mimetics carrying either catecholate moieties (1) or hydroxypyridinone groups (2) as iron chelators. These siderophore-like molecules were prepared in no more than four steps with good global yields. The physicochemical study has highlighted a strong iron affinity since their pFe values were higher than 20. 1 possesses even a pFe value superior than those of pyoverdine, the P. aeruginosa endogenous siderophore, suggesting its potential ability to compete with it. At physiological pH, 1 forms mainly a 2:3 complex with iron, whereas two species are observed for 2. Unfortunately, the corresponding Ga(III)-1 and 2 complexes showed no antibacterial activity against P. aeruginosa DSM 1117 strain. The evaluation of their siderophore-like activity showed that 1 and 2 could be internalized by the bacteria.

Thermodynamic stability and kinetic inertness of a Gd-DTPA bisamide complex grafted onto gold nanoparticles.

Gold nanoparticles coated by gadolinium (III) chelates (Au@DTDTPA) where DTDTPA is a dithiolated bisamide derivative of diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA), constituted contrast agents for both X-ray computed tomography and magnetic resonance imaging. In an MRI context, highly stable Gd(3+) complexes are needed for in vivo applications. Thus, knowledge of the thermodynamic stability and kinetic inertness of these chelates, when grafted onto gold nanoparticles, is crucial since bisamide DTPA chelates are usually less suited for Gd(3+) coordination than DTPA. Therefore, these parameters were evaluated by means of potentiometric titrations and relaxivity measurements. The results showed that, when the chelates were grafted onto the nanoparticle, not only their thermodynamic stability but also their kinetic inertness were improved. These positive effects were correlated to the chelate packing at the nanoparticle surface that stabilized the corresponding Gd(3+) complexes and greatly enhanced their kinetic inertness.

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 ßZnLH = 28.1 and log ßGdLH = 32.1.

Tetraphosphonated thiophene ligand: mixing the soft and the hard.

The synthesis of ligand L(T)H8, based on a thiophene framework containing two bis(aminomethyldiphosphonate) functions in the ortho position to the central sulfur atom, is described, together with the characterization of the intermediate compounds. The physico-chemical properties of the ligand were first studied by means of potentiometry and UV-Vis absorption spectrophotometric titrations to determine its pK values. Six successive equilibrium constants were determined in aqueous solutions. The same means were then used to quantify the interactions of the ligand with Ni(II), Cu(II) and Zn(II). Following the conventional Irving-Williams trend, L(T) was shown to have the highest affinity towards Cu(II) (log K(CuL(T)) = 16.11(3)), while Zn(II) and Ni(II) showed similar values (log K(ML(T)) = 10.81(8) and 10.9(1), respectively), revealing a large selectivity of L(T) toward Cu(II). Based on a combination of UV-Vis absorption spectroscopy and EPR measurements as a function of pH, along with DFT calculations, the coordination behavior of the hard phosphonate, medium amino and soft thiophene entities are questioned regarding their coordination to the Cu atom.

A modified cyclen azaxanthone ligand as a new fluorescent probe for Zn2+.

A new cyclen derivative L, bearing a methyl-chromeno-pyridinylidene hydrazone moiety, was synthesized and studied in MeOH, as potential fluorescent "OFF-on-ON" sensors for Zn(ii). Photophysical properties of this ligand being PET regulated, L was only weakly emissive in the absence of metal ions (OFF). L fluorescence was increased modestly upon addition of one equivalent of Zn(II), and further increased upon addition of a second equivalent. Therefore, Zn : L behaved as a highly sensitive ON sensor for zinc. This efficiency was correlated to Zn(II) coordination via the hydrazone moiety of the fluorophore, producing an efficient CHelation-Enhanced Fluorescence (CHEF) effect. A complementary theoretical study carried out with DFT calculations further elucidated the optical properties.

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 logß110 =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.

Cyclam-methylbenzimidazole: a selective OFF-ON fluorescent sensor for zinc.

The coordination properties and the photophysical response of a new cyclam fluorescent probe for Zn(II), [L1H: 1-(benzimidazol-2-ylmethyl]-1,4, 8,11-tetraazacyclotetradecane] toward Cu(II), Zn(II), and Cd(II) are reported. The stability constants of the corresponding complexes were determined by means of potentiometric measurements in aqueous solution. The fluorescence of L1H was quenched by the presence of Cu(II), and L1H behaves as an OFF-ON sensor for Zn(II) even in the presence of a wide range of biological divalent cations. Furthermore, on addition of successive amounts of Zn(II), the fluorescence emission of L1H increases linearly by a factor of 12. This can be correlated to the efficient Zn(II) binding of L1H and to the participation of all the amine functions in the metal coordination which prevents the photoinduced electron transfer (PET) effect and promotes a good chelation-enhanced fluorescence (CHEF) effect; this confers to the cyclam probe better sensing properties than the cyclen ionophore.