Isomeric Effect on the Pharmacokinetic Behavior of Anticancer CuII Mixed Chelate Complexes: Experimental and Theoretical Approach

We present herein the results of a pharmacokinetic (PK) study of Cu-II mixed-chelate coordination compound CasIII-La {[Cu(5,6-dimethyl-1,10-phenanthroline)(acetylacetonate)( H2O)] NO3}, which belongs to the antineoplastic family of compounds known as Casiopenas. The main interest in this molecule lies in the big difference in its lethal dose and PK parameters in Wistar rats compared with its structural isomer CasIII-Ea {[Cu(4,7-dimethyl-1,10-phenanthroline)(acetylacetonate)(H2O)]NO3}. For instance, the half-lives of these compounds are 9.6 +/- 1.15 and 48 +/- 4.6 h for CasIII-La and CasIII-Ea, respectively. The differences in the half- lives have been attributed to their different capacities to cross cellular membranes. Molecular dynamics studies of a fraction of a cell membrane and Casiopenas were developed to identify the possible intermolecular interactions responsible for the retention of the compound inside the cellular membrane. Also, quantum theory of atoms-in-molecules studies was developed to determine the capacity of the hydrogen atoms of methyl groups to participate in intermolecular interactions. In addition, peripheral human blood lymphocyte and macrophage samples were used to determine the cross-membrane effect on cytotoxicity.