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

Chiara Pelosi, Francesca Saitta, Caterina Zerino, Giovanni Canil, Tarita Biver, Alessandro Pratesi, Celia Duce, Dimitrios Fessas, Chiara Gabbiani, Maria Rosaria Tiné

Molecules (Basel, Switzerland) 2021 Apr 19

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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.

Citation

Chiara Pelosi, Francesca Saitta, Caterina Zerino, Giovanni Canil, Tarita Biver, Alessandro Pratesi, Celia Duce, Dimitrios Fessas, Chiara Gabbiani, Maria Rosaria Tiné. Thermodynamic Evaluation of the Interactions between Anticancer Pt(II) Complexes and Model Proteins. Molecules (Basel, Switzerland). 2021 Apr 19;26(8)