High Resolution Image Download MS PowerPoint Slide Two new decadentate macrocyclic chelators, bpycropa and phencropa, were synthesized by incorporating 2,2′-bipyridine and 1,10-phenanthroline units, respectively, into the picolinate-functionalized aza-crown ether scaffold of macropa, with the aim of enhancing cavity preorganization for heavy alkaline earth metal complexation. Both ligands and their barium complexes, employed as nonradioactive surrogates for radium-223, were characterized by NMR spectroscopy, mass spectrometry, potentiometric titrations, X-ray crystallography, and DFT calculations. Solid-state structures revealed asymmetric coordination geometries markedly different from the more symmetric arrangement in Ba( macropa ), reflecting conformational constraints imposed by the aromatic fragments. Under physiologically relevant conditions, phencropa exhibited thermodynamic stability toward Ba(II) comparable to macropa (pBa = 11.7 vs 11.6), while bpycropa showed lower affinity (pBa = 10.0). Kinetic studies demonstrated enhanced inertness for both systems relative to macropa, with dissociation half-lives of 71.3 min for Ba( bpycropa ) and 160.5 min for Ba( phencropa ) compared to 21 min for Ba( macropa ) (20 °C, pH 7.4, 10 mM, I = 0.15 M NaCl). Despite these promising results, radiolabeling studies with radium-223 revealed that neither chelator achieved the serum stability of 223 RaRa- macropa, highlighting the delicate interplay between preorganization, donor atom composition, and kinetic inertness required for effective radium coordination and offering design principles for next-generation chelators.
Merdžo et al. (Wed,) studied this question.