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

Abstract

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 (L^a) have been studied at 25 °C and an ionic strength of 0.15 mol dm⁻³. Copper forms more stable complexes with L^a 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 [CuL^aH₋₁] and pentadentate binding in [CuL^aH₋₂]. Octanol–water partition coefficients of Cu(II)–L^a complexes indicate that although these species are largely hydrophilic, approximately 5.62% of the [CuL^aH₋₁] complex goes into the organic phase. This percentage may promote dermal absorption of copper with a calculated penetration rate of 3.75 × 10⁻⁴ mm h⁻¹. The [CuL^aH₋₁] species which predominates at pH 7.4 is a poor mimic of native copper–zinc superoxide dismutase. Blood-plasma simulation studies predict that L^a 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.