DNA, a target of mixed chelate copper(II) compounds (Casiopeinas®) studied by electrophoresis, UV-vis and circular dichroism techniques.

Casiopeinas are a family of mixed chelate copper(II) complexes with antiproliferative and antineoplastic activities, results that have positioned them as an alternative for cancer treatment. Because DNA is one of their principal targets, it is of our interest to find out the effect of substituents on the diiamine ligands over mode of interaction. Therefore, we studied 21 Casiopeinas upon DNA by gel electrophoresis, UV-vis and circular dichroism (CD) spectroscopic techniques, previously studied by DFT calculations and Quantitative Structure-Activity Relationship (QSAR). According to electrophoresis results, the interaction modes between Casiopeinas with DNA may be through the intercalation or in the minor groove. UV-vis spectroscopy showed a hypochromic or hyperchromic effect as a consequence of each interaction. The analysis suggests the binding along the minor groove and intercalation are both influenced by the substituents in the diimine ligands and depend on the nature of the secondary moiety (acetylacetonate or glycinate). Additionally, a new band in electrophoresis and CD spectra suggests adducts formation. In general, we prove that molecules with the highest molecular weight, electron donating substituents and glycinate as secondary ligand are intercalating agents; unlike molecules with electron withdrawing substituents as chloride or nitro and acetylacetonate as secondary ligand which interact in the minor groove.

Synergistic effects between a copper-based metal Casiopeína III-ia and cisplatin.

Additive, subadditive or superadditive interactions observed in combination therapy play an important role in several treatments, particularly for cancer. The isobolographic analysis allows to establish the pharmacological interactions that exist between two drugs that are administered together in equieffective doses. In order to identify if the combination of two compounds presents synergistic interaction, the antiproliferative activity of CasIII-ia with analogue compounds or cisplatin in different molar ratios was evaluated. Results showed that this compound exhibited additive, subadditive or antagonic and superadditive or synergistic interactions, depending on the compound that accompanies it and the proportion of the compounds in the combination. One of the combinations increased the antiproliferative activity from 50 to 77% when the cells were exposed to 4.59 and 9.70 µM to CasIII-ia and cisplatin, respectively. Further studies of the toxicity and biochemical level of the interactions still remain to be studied on a in-vivo xenographed model.