Solution chemistry of 1,15-bis(N,N-dimethyl)-5,11-dioxo-8-(N-benzyl)-1,4,8,12,15-pentaazapentadecane with metal ions of biological interest-Insights toward active metal ion containing therapeutics and diagnostic agents.

The equilibrium constants of Cu(II), Zn(II), Ca(II) and Gd(III) with 1,15-bis(N,N-dimethyl)-5,11-dioxo-8-(N-benzyl)-1,4,8,12,15-pentaazapentadecane (La) have been studied at 25 degrees C and an ionic strength of 0.15 mol dm-3. Copper forms more stable complexes with La than the other metal ions investigated. This is probably due to the ease with which Cu(II) deprotonates the nitrogen donor atoms of the amide groups. UV/Vis spectrophotometric data indicate tetradentate binding of the ligand towards copper in [CuLaH-1] and pentadentate binding in [CuLaH-2]. Octanol-water partition coefficients of Cu(II)-La complexes indicate that although these species are largely hydrophilic, approximately 5.62% of the [CuLaH-1] complex goes into the organic phase. This percentage may promote dermal absorption of copper with a calculated penetration rate of 3.75x10(-4) mm h-1. The [CuLaH-1] species which predominates at pH 7.4 is a poor mimic of native copper-zinc superoxide dismutase. Blood-plasma simulation studies predict that La is unable to increase the low molecular mass copper fraction in vivo. This has been confirmed by biodistribution patterns, which are similar to those of 64CuCl2.

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.

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 degrees 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 x 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.