Thermodynamic and biodistribution studies of Zn(ii), Ca(ii), Gd(iii) and Cu(ii) complexes of 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime

Abstract

The thermodynamic equilibria of copper(II), zinc(II), calcium(II) and gadolinium(III) with 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime (L¹) have been studied at 25 °C and an ionic strength of 0.15 mol dm⁻³. Copper and gadolinium form stable complexes with the ligand while the corresponding zinc species are more than 9 log units less stable. No complexes between calcium and the ligand were detected. The low binding strength of L¹ towards zinc is attributed to the square-planar coordination geometry forced on the metal ion by the ligand as revealed by molecular mechanics calculations and molecular dynamics simulations. Speciation calculations, using a computer model of blood plasma, indicate that, despite the high concentration of zinc(II) and calcium(II) in vivo, L¹ is able to increase the low-molecular-mass fraction of copper in plasma. Octanol/water partition coefficient of [CuL¹H₋₁] indicates that although this species is largely hydrophilic, approximately 6% of the complex goes into the octanol phase and hence may promote dermal absorption of copper by the same amount. The dermal penetration rate is calculated to be 4.0 × 10⁻⁴ mm h⁻¹. The [CuL¹H₋₁] complex, which predominates at pH 7.4, is a poor mimic of native copper–zinc superoxide dismutase. Biodistribution experiments using the ⁶⁴Cu-labelled [CuL¹H₋₁] complex indicate an initial high uptake of this species in the liver followed by redistribution into muscle. Only a small amount is excreted through the urine.