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Is Less More? Influence of the Coordination Geometry of Copper(II) Picolinate Chelate Complexes on Metabolic Stability.

ABSTRACT: A growing number of copper(II) complexes have been identified as suitable candidates for biomedical applications. Here, we show that the biocompatibility and stability of copper(II) complexes can be tuned by directed ligand design and complex geometry. We demonstrate that azamacrocycle-based chelators that envelope copper(II) in a five-coordinate, distorted trigonal-bipyramidal structure are more chemically inert to redox-mediated structural changes than their six-coordinate, Jahn-Teller-distorted counterparts, as evidenced by electrochemical, crystallographic, electron paramagnetic resonance, and density functional theory studies. We further validated our hypothesis of enhanced inertness in vitro and in vivo by employing Cu-64 radiolabeling of bifunctional analogues appended to a prostate-specific membrane antigen targeting dipeptide. The corresponding Cu-64 complexes were tested for stability in vitro and in vivo, with the five-coordinate system demonstrating the greatest metabolic stability among the studied picolinate complex series.

SUBMITTER: Vaughn BA

PROVIDER: S-EPMC9199361 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Is Less More? Influence of the Coordination Geometry of Copper(II) Picolinate Chelate Complexes on Metabolic Stability.

Vaughn Brett A BA Brown Alexander M AM Ahn Shin Hye SH Robinson Jerome R JR Boros Eszter E

Inorganic chemistry 20201028 22

A growing number of copper(II) complexes have been identified as suitable candidates for biomedical applications. Here, we show that the biocompatibility and stability of copper(II) complexes can be tuned by directed ligand design and complex geometry. We demonstrate that azamacrocycle-based chelators that envelope copper(II) in a five-coordinate, distorted trigonal-bipyramidal structure are more chemically inert to redox-mediated structural changes than their six-coordinate, Jahn-Teller-distort ...[more]

PMID: 33112609

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Project description:The nature of the ligand is an important aspect of controlling the structure and reactivity in coordination chemistry. In connection with our study of heme-copper-oxygen reactivity relevant to cytochrome c oxidase dioxygen-reduction chemistry, we compare the molecular and electronic structures of two high-spin heme-peroxo-copper [Fe(III)O(2)(2-)Cu(II)](+) complexes containing N(4) tetradentate (1) or N(3) tridentate (2) copper ligands. Combining previously reported and new resonance Raman and EXAFS data coupled to density functional theory calculations, we report a geometric structure and more complete electronic description of the high-spin heme-peroxo-copper complexes 1 and 2, which establish mu-(O(2)(2-)) side-on to the Fe(III) and end-on to Cu(II) (mu-eta(2):eta(1)) binding for the complex 1 but side-on/side-on (mu-eta(2):eta(2)) mu-peroxo coordination for the complex 2. We also compare and summarize the differences and similarities of these two complexes in their reactivity toward CO, PPh(3), acid, and phenols. The comparison of a new X-ray structure of mu-oxo complex 2a with the previously reported 1a X-ray structure, two thermal decomposition products respectively of 2 and 1, reveals a considerable difference in the Fe-O-Cu angle between the two mu-oxo complexes ( angleFe-O-Cu = 178.2 degrees in 1a and angleFe-O-Cu = 149.5 degrees in 2a). The reaction of 2 with 1 equiv of an exogenous nitrogen-donor axial base leads to the formation of a distinctive low-temperature-stable, low-spin heme-dioxygen-copper complex (2b), but under the same conditions, the addition of an axial base to 1 leads to the dissociation of the heme-peroxo-copper assembly and the release of O(2). 2b reacts with phenols performing H-atom (e(-) + H(+)) abstraction resulting in O-O bond cleavage and the formation of high-valent ferryl [Fe(IV)=O] complex (2c). The nature of 2c was confirmed by a comparison of its spectroscopic features and reactivity with those of an independently prepared ferryl complex. The phenoxyl radical generated by the H-atom abstraction was either (1) directly detected by electron paramagnetic resonance spectroscopy using phenols that produce stable radicals or (2) indirectly detected by the coupling product of two phenoxyl radicals.

Dataset Information

Is Less More? Influence of the Coordination Geometry of Copper(II) Picolinate Chelate Complexes on Metabolic Stability.

Publications

Is Less More? Influence of the Coordination Geometry of Copper(II) Picolinate Chelate Complexes on Metabolic Stability.

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