Phosphonate Chelators for Medicinal Metal Ions

Abstract

A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)­pharmaceuticals. Three ligands (H6phospa, H6dipedpa, H6eppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of H6phospa and H6dipedpa. 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, H6phospa was noted to form the most stable complexes, and H6eppy 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 H6phospa and H6dipedpa complexes with La3+ and Sc3+. A comparison of experimental 1H NMR spectra with calculated 1H 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.

Polymeric Copper Chelator for Long-term Inhibition of Breast Cancer Proliferation and Lung Metastasis

“…Typical examples are 1,2-dihydropyrimidines by the Biginelli reaction 38 and α-aminophosphonates by the K−F reaction. 39,40 Polymers containing these groups can be easily prepared, and these polymers are potential polymer copper chelators. (2) Many MCRs are compatible with reversible addition− fragmentation chain transfer (RAFT) polymerization, 41−44 a well-known controlled radical polymerization (CRP) technology.…”

Polymer Chelator Prepared via the Kabachnik–Fields Reaction for the In Vivo Prevention of Heavy-Metal Damage

“…Recently, multicomponent reactions (MCRs) have been used to synthesize new polymers. Typical examples of these MCRs are the Passerini, Ugi, Kabachnik–Fields (K–F), Biginelli, and Hantzsch reactions, as well as alkyne-based and metal-catalyzed MCRs. − We believe that MCRs may overcome the restrictions in developing safe and effective polymer chelators because certain MCRs generate products with metal-chelating capability (α-aminophosphonates by the K–F reaction , and dihydropyrimidines by the Biginelli reaction), and polymers prepared by these MCRs are potential polymer chelators. Many MCRs are compatible with chelating groups; therefore, monomers containing chelating groups can be simply prepared through one step via these MCRs, which greatly simplifies the preparation of monomers and related polymer chelators.…”

“…The K–F reaction, introduced by M. I. Kabachnik and E. K. Fields in 1952, effectively produces α-aminophosphonates using three common components (aldehyde, amine, and phosphite). , This reaction has been broadly studied in organic and pharmaceutical chemistry because α-aminophosphonates exhibit many important bioactivities , and are potential chelating groups for various metals. , Recently, the K–F reaction has been used to develop new functional polymers. ,, However, polymer chelators prepared via the K–F reaction to prevent heavy-metal poisoning in vivo are uncommon.…”

“…46,47 This reaction has been broadly studied in organic and pharmaceutical chemistry because α-aminophosphonates exhibit many important bioactivities 48,49 and are potential chelating groups for various metals. 43,44 Recently, the K−F reaction has been used to develop new functional polymers. 40,41,50 However, polymer chelators prepared via the K−F reaction to prevent heavy-metal poisoning in vivo are uncommon.…”

Nickel-Catalyzed Defluorophosphonylation of Aryl Fluorides

“…In these S N Ar-type reactions, the pronucleophiles are limited to secondary phosphines and phosphine oxides; the successful use of more electron-deficient phosphonic acid diesters [HP­(O)­(OR) 2 ] has not been reported. Organophosphonic acids [RP­(O)­(OH) 2 ] and their derivatives are widely used as drugs or prodrugs, chelators of metallic salts, surface modifiers, and phosphoantigens . Thus, the development of a phosphonylation reaction for aryl fluorides is in demand.…”