Thermodynamic Evaluation of the Interactions between Anticancer Pt(II) Complexes and Model Proteins

In this work, we have analysed the binding of the Pt(II) complexes ([PtCl(4′-phenyl-2,2′:6′,2″-terpyridine)](CF3SO3) (1), [PtI(4′-phenyl-2,2′:6′,2″-terpyridine)](CF3SO3) (2) and [PtCl(1,3-di(2-pyridyl)benzene) (3)] with selected model proteins (hen egg-white lysozyme, HEWL, and ribonuclease A, RNase A). Platinum coordination compounds are intensively studied to develop improved anticancer agents. In this regard, a critical issue is the possible role of Pt-protein interactions in their mechanisms of action. Multiple techniques such as differential scanning calorimetry (DSC), electrospray ionization mass spectrometry (ESI-MS) and UV-Vis absorbance titrations were used to enlighten the details of the binding to the different biosubstrates. On the one hand, it may be concluded that the affinity of 3 for the proteins is low. On the other hand, 1 and 2 strongly bind them, but with major binding mode differences when switching from HEWL to RNase A. Both 1 and 2 bind to HEWL with a non-specific (DSC) and non-covalent (ESI-MS) binding mode, dominated by a 1:1 binding stoichiometry (UV-Vis). ESI-MS data indicate a protein-driven chloride loss that does not convert into a covalent bond, likely due to the unfavourable complexes’ geometries and steric hindrance. This result, together with the significant changes of the absorbance profiles of the complex upon interaction, suggest an electrostatic binding mode supported by some stacking interaction of the aromatic ligand. Very differently, in the case of RNase A, slow formation of covalent adducts occurs (DSC, ESI-MS). The reactivity is higher for the iodo-compound 2, in agreement with iodine lability higher than chlorine

Pt(II) complexes as potential precursors of anticancer agents and their interaction with model proteins

Over the past 30 years, platinum-based drugs, particularly cisplatin and carboplatin, have been widely used in chemotherapy to treat various cancers. The use of cisplatin is limited by the presence of several side effects and by the development of long-term cisplatin resistance. For this reason, the research is looking for new platinum-based anticancer drugs to improve the clinical performance of cisplatin. In addition, the interaction of anticancer platinum complexes with proteins is of great importance, since the proteins have multiple functions in the activity of cisplatin and they are involved in many stages of the cytotoxic process. In this project three metal complexes based on Pt(II) were synthesized and their interaction with two model proteins (lysozyme and ribonuclease A) were studied, using differential scanning calorimetry, UV-Vis absorption titrations and mass spectrometry. Based on the results obtained, the compound 1 and the compound 2 interact strongly with the model proteins by coordination with cysteine or histidine residues, while the compound 3 interacts only weakly with the model proteins. Furthermore, binding constants and thermodynamic parameters were calculated by differential scanning calorimetry. The calorimetric binding constants were compared with those obtained by spectroscopic studies