Interactions of arene-Ru(II)-chloroquine complexes of known antimalarial and antitumor activity with human serum albumin (HSA) and transferrin

The interactions of π-arene-Ru(II)-chloroquine complexes with human serum albumin (HSA), apotransferrin and holotransferrin have been studied by circular dichroism (CD) and UV-Visible spectroscopies, together with isothermal titration calorimetry (ITC). The data for Ru(η⁶-p-cymene)(CQ)(H₂O)Cl]PF₆ (1), Ru(η⁶-benzene)(CQ)(H₂O)Cl]PF₆ (2), Ru(η⁶-p-cymene)(CQ)(H₂O)₂]PF₆]₂ (3), Ru(η⁶-p-cymene)(CQ)(en)]PF₆]₂ (4), Ru(η⁶-p-cymene)(η⁶-CQDP)]BF₄]₂ (5) (CQ: chloroquine; DP: diphosphate; en: ethylenediamine), in comparison with CQDP and Ru(η⁶-p-cymene)(en)Cl]PF₆] (6) as controls demonstrate that 1, 2, 3, and 5, which contain exchangeable ligands, bind to HSA and to apotransferrin in a covalent manner. The interaction did not affect the α-helical content in apotransferrin but resulted in a loss of this type of structure in HSA. The binding was reversed in both cases by a decrease in pH and in the case of the Ru-HSA adducts, also by addition of chelating agents. A weaker interaction between complexes 4 and 6 and HSA was measured by ITC but was not detectable spectroscopically. No interactions were observed for complexes 4 and 6 with apotransferrin or for CQDP with either protein. The combined results suggest that the arene-Ru(II)-chloroquine complexes, known to be active against resistant malaria and several lines of cancer cells, also display a good transport behavior that makes them good candidates for drug development.