Synthetic, structural, and stability studies of metal complexes of cross-bridged tetraamine macrocycles.

摘要

Cross-bridging of tetraazamacrocyclic ligands with an ethylene unit forms a family of bicyclic tetraamine ligands originally designed and synthesized by the Weisman-Wong research group to selectively complex small metal ions such as Li+ in a cis-folded configuration. Cu(II), Ga(III), and In(III) complexes of these cross-bridged ligands have potential radiometal-based pharmaceutical applications due to their high kinetic stabilities. Cu(II) complexes of eight cross-bridged tetraazamacrocyclic ligands have been synthesized and structurally characterized. Their relative kinetic stabilities were evaluated by monitoring acid-promoted dissociation processes using UV-Vis spectroscopy. The copper complex of a dicarboxylate pendant-armed cross-bridged cyclam was the most inert, consistent with its superior in vivo stability. This is also in accord with the fact that copper fits best in this ligand as indicated by the largest N_ax-Cu-N _ax bond angle of this complex compared to other six-coordinate Cu(II) complexes of cross-bridged ligands. Ga(III) and In(III) complexes of three of the ligands have been prepared and characterized. The indium complex of cross-bridged cyclen with the poorest fit in the solid-state showed the lowest inertness as indicated by its partial decomplexation in water. By contrast, gallium complexes of cross-bridged cyclam (ligand 1) and a dicarboxylate pendant-armed cross-bridged cyclen have been found to be stable in acidic D₂O (pD = 1.07) for more than seven months. Thus we were able to investigate the possible solution structures of the Ga(III) complex of ligand 1 in acidic D₂O using NMR techniques. Zn(II), Cd(II) and Hg(II) complexes of the eight cross-bridged ligands have been synthesized and whenever appropriate, structurally characterized. Comparison of their solid-state structures suggested the selectivity of this family of cross-bridged ligands for Zn(II) ion based on its best fit inside the cleft formed by the cross-bridged ligands. In addition, the kinetic stabilities of selected Zn(II), Cd(II) and Hg(II) complexes were studied. As with copper and indium complexes, the Zn(II) complex of cross-bridged cyclam is more inert than that of cross-bridged cyclen. These results indicate that cross-bridged cyclam and its derivatives have more potential for radiopharmaceutical applications than related cross-bridged cyclen and its derivatives.