Phosphonate Chelators for Medicinal Metal Ions

A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)-pharmaceuticals. Three ligands (H(6)phospa, H(6)dipedpa, H(6)eppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of H(6)phospa and H(6)dipedpa. NMR spectroscopy techniques were used to confirm the complexation of each ligand with selected trivalent metal ions. These methods were particularly useful in discerning structural information for Sc3+ and La3+ complexes. Solution studies were conducted to evaluate the complex stability of 15 metal complexes. As a general trend, H(6)phospa was noted to form the most stable complexes, and H(6)eppy associated with the least stable complexes. Moreover, In3+ complexes were determined to be the most stable, and complexes with La3+ were the least stable, across all metals. Density functional theory (DFT) was employed to calculate structures of H(6)phospa and H(6)dipedpa complexes with La3+ and Sc3+. A comparison of experimental H-1 NMR spectra with calculated H-1 NMR spectra using DFT-optimized structures was used as a method of structure validation. It was noted that theoretical NMR spectra were very sensitive to a number of variables, such as ligand configuration, protonation state, and the number/orientation of explicit water molecules. In general, the inclusion of an explicit second shell of water molecules qualitatively improved the agreement between theoretical and experimental NMR spectra versus a polarizable continuum solvent model alone. Formation constants were also calculated from DFT results using potential-energy optimized structures. Strong dependence of molecular free energies on explicit water molecule number, water molecule configuration, and protonation state was observed, highlighting the need for dynamic data in accurate first-principles calculations of metal-ligand stability constants.