Solution equilibria of copper(II) complexation with N,N'-(2,2'-azanediylbis(ethane-2,1-diyl))dipicolinamide: a bio-distribution and dermal absorption study.

The protonation equilibria of a pentadentate ligand, N,N'-(2,2'-azanediylbis(ethane-2,1-diyl))dipicolinamide ([H(2)(5555)-N]) and the complexation of this ligand with Cu(II) Ca(II), Zn(II) and Ni(II) have been studied by pH-potentiometry, (1)H NMR spectroscopy and UV-vis spectrophotometry. (1)H NMR detected the protonation of the pyridyl groups and formation of Cu[H(2)(5555)-N]H species at low pH, while amide group deprotonation at higher pH resulted in the formation of Cu[H(2)(5555)-N]H(-1) and Cu[H(2)(5555)-N]H(-2) species in solution. Potentiometric detection of protonated species was limited by the acidic nature of the pyridyl nitrogen donors. From UV-vis spectroscopy it is suggested that the amide nitrogens are coordinated. This conclusion is supported by Molecular Mechanics calculations. Water-octanol partition coefficients for the Cu(II)-[H(2)(5555)-N] system indicated that although the Cu[H(2)(5555)-N]H(-1) species is largely hydrophilic, approximately 54% of the complex goes into the organic phase. This percentage is able to promote dermal absorption of copper with a calculated penetration rate of 1.92x10(-1)cmh(-1). This was confirmed by dermal absorption studies which illustrate the role of hydrophobicity in promoting percutaneous drug administration.