Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Kinetic, Relaxometric, Density Functional Theory, and Superoxide Dismutase Activity Studies

Abstract

We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms at either positions 3,6 (<b>3,6-PC2A</b>) or 3,9 (<b>3,9-PC2A</b>) of the macrocyclic fragment. The <b>3,6-PC2A</b> ligand was synthesized in five steps from pyclen oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with <b>3,9-PC2A</b> is characterized by a higher thermodynamic stability [log <i>K</i>_MnL = 17.09(2)] than the <b>3,6-PC2A</b> analogue [log <i>K</i>_MnL = 15.53(1); 0.15 M NaCl]. Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high ¹H relaxivities (<i>r</i>_1p = 2.72 and 2.91 mM^-1 s^-1 for the complexes with <b>3,6-PC2A</b> and <b>3,9-PC2A</b>, respectively, at 25 °C and 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (<i>k</i>_ex²⁹⁸) are 140 × 10⁶ and 126 × 10⁶ s^-1 for [Mn(<b>3,6-PC2A</b>)(H₂O)] and [Mn(<b>3,9-PC2A</b>)(H₂O)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with half-lives of 63 and 21 h, respectively, at pH = 7.4 in the presence of excess Cu(II). The <i>r</i>_1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)(H₂O)]^2- (H₄EDTA = ethylenediaminetetraacetic acid) and [Mn(PhDTA)(H₂O)]^2- (H₄PhDTA = phenylenediamine-<i>N</i>,<i>N</i>,<i>N</i>',<i>N</i>'-tetraacetic acid), indicating that the <b>PC2A</b> complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/<i>p</i>-nitro blue tetrazolium chloride assay at pH = 7.8. The Mn(II) complexes of <b>3,6-PC2A</b> and <b>3,9-PC2A</b> are capable of assisting decomposition of the superoxide anion radical. The kinetic rate constant of the complex of <b>3,9-PC2A</b> is smaller by 1 order of magnitude than that of <b>3,6-PC2A</b>.