In vitro and in vivo stability investigations of Cu(ii), Zn(ii), Ca(ii) and Gd(iii) complexes with N,N′-bis(2-hydroxyiminopropionyl) propane-1,3-diamine

Abstract

Formation constants of copper(II), zinc(II), calcium(II) and gadolinium(III) with N,N′-bis(2-hydroxyiminopropionyl) propane-1,3-diamine (L²) have been studied at 25 °C and an ionic strength of 0.15 mol dm⁻³. The reasonably high formation constants of the copper with this ligand are due to the ease with which the metal ion deprotonates the amide moieties. The square-planar coordination of L² towards copper as predicted from UV-visible data may also account for the high selectivity of L² towards the metal ion. Octanol/water partition coefficients of Cu(II)–L² complexes indicate that although these complexes are largely hydrophilic, approximately 1.86% of the [CuL²H₋₁] species goes into the octanol layer and hence may promote dermal absorption of copper with a calculated penetration rate of 1.24 × 10⁻⁵ cm h⁻¹. The [CuL²H₋₁] complex which predominates at pH 7.4 is a poor mimic of native copper–zinc superoxide dismutase. Blood-plasma simulation studies predict that, despite the high concentration of zinc and calcium in vivo, L² is able to increase the low-molecular-mass fraction of copper. Biodistribution experiments using ⁶⁴Cu-labelled [CuL²H₋₁] indicate an initial high uptake of this species in the liver, but it is predominantly excreted through the renal system.