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

Abstract

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.

DNA-binding, molecular docking studies and biological activity studies of ruthenium(ii) polypyridyl complexes

“…Several mechanisms have been proposed to elucidate the anticancer activities of ruthenium complexes, including the inhibition of metastasis, 23,24 interaction with DNA and proteins, 25,26 generation of ROS, 27 induction of apoptosis. 28 Based on our previous work, [29][30][31][32][33] we found that ruthenium(II) polypyridyl complexes appear to show high activity against cancer cells.…”

Interaction of manganese(II) complex with apotransferrin and the apotransferrin enhanced anticancer activities

“…The binding constant of AdpaMn (K A = 1.86 Â 10 5 M À1 ) is much bigger than that of MnCl 2 , which is similar to that of Ru(II)-complex with transferrin (10 3 to 10 5 M À1 ) [10,22]. Stern-Volmer dynamic quenching constant of AdpaMn (K SV ) is 2.86 Â 10 5 M À1 , which is greater than that of biological macromolecules (K SV < 100 M À1 ), indicating the possible formation of AdpaMn-apoTf complex entity [22,23]. Further, the effect of the other function-related proteins in serum, such as human serum albumin (HSA), on the binding of complexes to apoTf was studied (Fig.…”

Spectroscopic Study of the Interactions of Ruthenium-Ketoconazole Complexes of Known Antiparasitic Activity with Human Serum Albumin and Apotransferrin

“…21 Transferrin, in turn, is the protein primarily responsible for transporting iron throughout the body, and it can also bind metallodrugs reversibly. 23-25 In particular, ruthenium complexes with anticancer 20,22,23 or antimalarial 26 properties have been shown to interact with human serum albumin (HSA) and with apotransferrin (ATf). We have now investigated the interactions of HSA and ATf with complexes 1-6 by use of a fluorimetric titration technique.…”

“…The values obtained for K indicate a fairly high affinity of the Ru-KTZ complexes for HSA, in the same order of magnitude as those observed by us for related Ru-chloroquine complexes with antimalarial activity. 26 …”

“…24,25 We have shown that such protein-drug interactions also take place with ruthenium-chloroquine complexes with antimalarial activity. 26 In this paper we report the results of a study on the binding of compounds 1-6 to HSA and to ATf through monitoring their ability to quench the inherent fluorescence of the tryptophan residues naturally present in the two proteins studied.…”