In vitro and in vivo studies of the dermally absorbed Cu(II) complexes of N5O2 donor ligands – Potential anti-inflammatory drugs

Copper complexes of N,N′-di(aminoethylene)-2,6-pyridinedicarbonylamine and bis-(N,N-dimethylethyl)-2,6-pyridinedicarboxamide have been studied by glass electrode potentiometry, NMR, UV and IR spectroscopy as potential anti-inflammatory agents for the alleviation of inflammation associated with rheumatoid arthritis. The protonation and formation constants with Cu(II), Zn(II) and Ca(II), determined at 25 °C and an ionic strength of 0.15 mol dm−3 were used to calculate the copper plasma mobilizing index of the ligands. Spectroscopic studies suggested that metal ion complexation promotes deprotonation and coordination of the amide nitrogens resulting in overall tetragonal distorted copper complexes. Bio-distribution and dermal absorption studies showed the complexes to have relatively long biological half-lives with 50% of the injected dose remaining in the body 24 h after administration.

Previous studies have shown that diamidediamine ligands are not able to mobilize copper(II) in vivo. In order to improve the thermodynamic stability of the complexes a pyridyl group has been inserted into the ligand. We report the in vitro speciation and stability constants of two such ligands. NMR, IR, and UV–Vis spectroscopy was used to postulate structures for the different species formed in solution. Bio-distribution and dermal absorption studies showed the complexes to have relatively long biological half-lives with 50% of the injected dose remaining in the body 24 h after administration.Figure optionsDownload as PowerPoint slide