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 trigonalbipyramidal 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.

Versatile Activity of a Copper(II) Complex Bearing a N4‐Tetradentate Schiff Base Ligand with Reduced Oxygen Species

“…= 2.06, characteristic of a Cu(II) coordination geometry with a N 4square-planar base (Figure 4(a,b)). [16] Therefore, after reaction with O 2 *À , Cu(II) ion retains the distorted square-pyramidal geometry, [26] and exhibits a well-defined N-superhyperfine (shf) pattern with a N = 11.5 × 10 À 4 cm À 1 in the perpendicular region of the spectrum (Figure 4, inset). The observation of the shf pattern is probably due to the higher ionic strength after addition of KO 2 that favors the formation of a good glass and thus better resolved lines.…”

“…[55] When the complex is left to react with H 2 O 2 in DMF and the reaction mixture is frozen, the low-temperature X-band EPR spectrum displays the characteristic pattern of distorted squarepyramidal Cu(II) complexes (Figure 7b). [16,26] Inspection of the spectrum reveals the presence of two paramagnetic species with two sets of g k values with distinct A k . Spectral deconvolution afforded g k 1 = 2.25, A k 1 = 187 × 10 À 4 cm À 1 , g ?…”

“…[17][18][19][20][21][22][23][24] In the Cu(II)/Cu(I) redox chemistry, the metal activity is strongly affected by the environment around the metal center because electron transfer involves changes in the coordination number and geometry. [25][26] When switching between both oxidation states small structural reorganization is usually required for fast electron transfer, which depends on the rigidity/flexibility of the ligand. [27,28] In copper complexes of the N,N'-bis(2-pyridinylmethylen)alkane-1,n-diamine family, the Cu-(II)/Cu(I) redox potential and geometry can be tuned by the length of the alkyl chain between the two imino N-atoms.…”

Dynamic Coordination between a Triphenylamine-Functionalized Salicylaldehyde Schiff Base and a Copper(II) Ion

“…The average Cu−N bond length (1.96 Å) observed for 2TPA-Py@ 4Cu is shorter than that for TPA-Py@Cu (1.98 Å), and the versatile coordination chemistry of the copper center allows it to readily bind in five-coordinate fashion to 2TPA-Py@4Cu, which is thought to be the preferred thermodynamic bonding mode versus possible four-coordinate complex TPA-Py@Cu. 46 Moreover, although the atomic radius of zinc(II) (74 pm) is approximately equal to that of copper(II) (73 pm), the Zn−N bond is typically longer than the Cu−N bond. 47,48 Thus, we tentatively attribute the increased affinity of the copper(II) ion herein to the increased electron affinity for the nitrogen atom versus that for the other metal ions for nitrogen, and its versatile coordination chemistry.…”

Metal ion size profoundly affects H3glyox chelate chemistry

“…25 Similarly, Cu 2+ complexes of monopicolinate derivatives of cyclen and cyclam, and [Cu(nompa)] + (Chart 1) all exhibit ve-coordinate Cu 2+ ion. 26,27 Table S5 † presents the calculated bond distances from the DFT structures. Compared to the Cu-O(ox) bond distance of 2.142Å in the reported [Cu(hox)] structure, 28 the Cu-O(ox) bond is slightly shorter in [Cu(glyox)] À complex with an average Cu-O(ox) bond distance of 2.006Å.…”