Maria de Guadalupe Jaraquemada-Pelaez

Zinc(II) and copper(II) complexes with hydroxypyrone iron chelators.

High stability of the complexes formed at physiological pH is one of the basic requisites that a good iron chelator must possess. At the same time the chelating agent must be selective toward iron, i.e., the stability of iron complexes must be significantly higher than that of the complexes formed with essential metal ions, in order that these last ones do not perturb iron chelation. In the frame of our research on iron chelators we have designed and synthesized a series of tetradentate derivatives of kojic acid, and examined their binding properties toward Fe(3+) and Al(3+). In this paper, for a characterization of the behavior of the proposed iron chelating agents in biological fluids, their complex formation equilibria with copper(II) and zinc(II) ions have been fully characterized together with a speciation study, showing the degree at which the iron chelators interfere with the homeostatic equilibria of these two essential metal ions.

Di- and Trivalent Metal-Ion Solution Studies with the Phosphinate-Containing Heterocycle DEDA-(PO)

A 7-membered triprotic heterocycle, DEDA-(PO), was synthesized, characterized, and tested for its solution properties with three trivalent lanthanides (La3+, Gd3+, and Lu3+) and three biologically relevant divalent metal ions (Ca2+, Zn2+, and Cu2+). The ligand synthesis has been reported once before; however, the characterization results were previously misinterpreted to correspond to a larger, 14-membered heterocycle, TETA-(PO)2. This manuscript serves to correct the original paper. Potentiometric titrations were carried out with each of the metal ions, and the thermodynamic stability values in terms of log β and log KML were calculated showing a 1:1 metal-to-ligand ratio preference for the divalent metal ions and a 1:2 ratio for the lanthanides. The stability of the 1:2 complexes decreased across the lanthanide series, presumed to be a steric effect. Further resolution to the potentiometry results was given via pH-dependent NMR spectrometry (with La3+) and pH-dependent UV-vis spectroscopy (with Cu2+), and the pM values were calculated for all metal ions. The solid-state structure of the 1:1 Cu2+-DEDA-(PO) complex was further characterized by X-ray crystallography.

Complex formation equilibria of Cu2+ and Zn2+ with Irbesartan and Losartan

&NA; We conducted a thorough study of Cu2 + complex formation equilibria with Irbesartan and Losartan, the two primary drugs for the cure of cardiovascular diseases, with the aim of recognising if these drugs could exert a chelating action towards Cu2 +. We used different complementary techniques to gain a clear picture of the involved protonation and complexation equilibria. The low solubility in water of the ligands and of the formed metal complexes prevented the use of water as solvent, so we had to perform the measurements in mixed methanol‐water solvents. Further, we studied the related equilibria with Zn2 + for evaluating a potential interference of this essential metal ion, largely present in biological fluids. Our study provided a strong evaluation of the formed complexes and of the relative stability constants. The binding of both metal ions takes place through the tetrazole moiety except for the Zn2 +‐Irbesartan system. In this last case, NMR measurements gave evidence of a tautomeric equilibrium involving the imidazole ring and the aliphatic chain. The estimated complexation model, and the related stability constants, allowed a speciation study in human plasma, based on a number of simplifying assumptions, which remarked that both drugs, Losartan and Irbesartan, could exert a chelating action, scavenging non‐negligible amounts of Cu2 + from the organism. Graphical abstract Figure. No caption available.

Looking at new ligands for chelation therapy

This work reports the synthesis, characterization and study of the complex formation equilibria of four new bis-kojic acid chelators with Fe3+, Al3+, Cu2+ and Zn2+. Based on previous encouraging results with tetradentate kojic acid derivatives, these ligands were designed with the aim of evaluating how acidic groups in the linker can affect both protonation constants and Fe3+ coordinating properties. Fe3+ and Al3+ complexation gave evidence of high metal-sequestering capacity, above all with the first metal ion. Complex formation equilibria with the essential metal ions Cu2+ and Zn2+ were furthermore studied to evaluate any disturbance of these chelating agents on the homeostatic equilibria of the essential metal ions. A multiplicity of techniques – potentiometry, UV-visible spectrophotometry, NMR spectroscopy and ESI-MS (electrospray ionization-mass spectrometry) – have enabled the characterization of the ligands, their corresponding metal complexes, together with an exhaustive analysis of the protonation and complex equilibria.

H4octox: Versatile Bimodal Octadentate Acyclic Chelating Ligand for Medicinal Inorganic Chemistry

H4octox, a versatile new octadentate acyclic chelating ligand, has been investigated as an alternative to the acyclic DTPA and the macrocyclic DOTA for trivalent metal ions useful in diagnostic medical imaging or therapeutic applications (Y3+, In3+, La3+, Gd3+, Lu3+). The synthesis of H4octox is straightforward in less steps and thus more economical than those of most previously reported chelators. Complex formation equilibria in the presence of Y3+, In3+, La3+, Gd3+, and Lu3+ revealed fast chelation and high metal-sequestering capacity. Quantitative labeling with 111In3+ was achieved within 15 min at room temperature at ligand concentrations as low as 10-7 M, exactly the properties required for the development of kit-based radiopharmaceuticals. In vitro serum stability studies and in vivo SPECT imaging confirmed excellent complex stability of [111In(octox)]-. Moreover, it is more lipophilic than most of the multidentate carboxylate- or picolinate-based chelators; it therefore shows more liver clearance and provides a complementary choice in the design of metal-based pharmaceuticals and in the tuning of their pharmacokinetic properties. Finally, H4octox showed a large fluorescence enhancement upon complexation with different metals, in particular, with Y3+ and Lu3+, which could be useful for non-radioactive fluorescent stability and cell studies as well as bimodal imaging. Excellent in vitro stability of [Y(octox)]- against transferrin and Fe3+ was confirmed employing this fluorescence.

Equilibrium studies of new bis-hydroxypyrone derivatives with Fe3+, Al3+, Cu2+ and Zn2+

This paper presents an easy and low cost synthesis of chelating agents for potential medical and environmental applications, and the evaluation of the stability of their complexes with Fe3+, Al3+, Cu2+ and Zn2+. In the last years, we synthesized and characterized effective iron chelators based on two kojic acid units joined by different linkers in position 6. In this study, we preserved kojic acid (a cheap and non-toxic molecule) as the basic unit but joined the two kojic acid units through ethylene diamine, propylene diamine and butylene diamine by reacting them with the OH groups in position 2. The different anchoring position of the linker, as well as the linker length, can affect both protonation and complex formation equilibria. A thorough study of the protonation and complex formation equilibria of the three ligands toward the metal ions is presented based on combined potentiometric and spectroscopic studies, and 1H NMR. The obtained results allow remarking that the orientation of the oxygen atoms in the kojic acid units, related to the anchoring position of the linker, strongly affects the protonation constants, while the chelating ability is practically unaffected. The trivalent metal ions form stable complexes with a 2:3 metal to ligand stoichiometry through the oxygen donor atoms of the ligands, whereas divalent metal ions form binuclear complexes for which the nitrogen atoms from the linker might be involved in the coordination sphere. The stability of the complexes decreases with linker length, and the selectivity of the ligands toward metal ions grows in the order Zn2+u202f<u202fCu2+u202f<u202fAl3+u202f<u202fFe3+.

H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals

An acyclic hexadentate oxine-derived chelating ligand, H2hox, was investigated as an alternative to current chelators for 68Ga. The straightforward preparation of H2hox, involving only one or two steps, obviates the synthetic challenges associated with many reported 68Ga chelators; it forms a Ga3+ complex of great stability (log K = 34.4) with a remarkably high gallium scavenging ability (pGa3+ = -log[Ga3+free] = 28.3, ([Ga3+] = 1 μM; [L x-] = 10 μM; pH 7.4, and 25 °C)). Moreover, H2hox coordinates 68Ga quantitatively in 5 min at room temperature in ligand concentrations as low as 1 × 10-7 M, achieving an unprecedented high molar activity of 11 ± 1 mCi/nmol (407 ± 3.7 MBq/nmol) without purification, suggesting prospective kit-based convenience. [68Ga(hox)]+ showed no decomposition in a plasma challenge. Good in vivo stability and fast renal and hepatic clearance of the [68Ga(hox)]+ complex were demonstrated using dynamic positron emission tomography/computed tomography imaging. The intrinsic fluorescence of [Ga(hox)]+ allowed for direct fluorescence imaging of cellular uptake and distribution, demonstrating the dual-channel detectability and intracellular stability of the metal complex.

p-NO2–Bn–H4neunpa and H4neunpa–Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and 111In Immuno-Single Photon Emission Computed Tomography Imaging

Potentially nonadentate (N5O4) bifunctional chelator p-SCN-Bn-H4neunpa and its immunoconjugate H4neunpa-trastuzumab for 111In radiolabeling are synthesized. The ability of p-SCN-Bn-H4neunpa and H4neunpa-trastuzumab to quantitatively radiolabel 111InCl3 at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In3+, Bi3+, and La3+ resulted in high conditional stability constant (pM) values. In vitro human serum stability assays have demonstrated both 111In complexes to have high stability over 5 days. Mouse biodistribution of [111In][In(p-NO2-Bn-neunpa)]-, compared to that of [111In][In(p-NH2-Bn-CHX-A″-diethylenetriamine pentaacetic acid (DTPA))]2-, at 1, 4, and 24 h shows fast clearance of both complexes from the mice within 24 h. In a second mouse biodistribution study, the immunoconjugates 111In-neunpa-trastuzumab and 111In-CHX-A″-DTPA-trastuzumab demonstrate a similar distribution profile but with slightly lower tumor uptake of 111In-neunpa-trastuzumab compared to that of 111In-CHX-A″-DTPA-trastuzumab. These results were also confirmed by immuno-single photon emission computed tomography (immuno-SPECT) imaging in vivo. These initial investigations reveal the acyclic bifunctional chelator p-SCN-Bn-H4neunpa to be a promising chelator for 111In (and other radiometals) with high in vitro stability and also show H4neunpa-trastuzumab to be an excellent 111In chelator with promising biodistribution in mice.