Abstract
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.
Highlights
In this work, we have analysed the binding of the Pt(II) complexes ([PtCl(4 -phenyl2,2 :6,2 -terpyridine)](CF3SO3) (1), [PtI(4 -phenyl-2,2 :6,2 -terpyridine)](CF3SO3) (2) and [PtCl(1,3di(2-pyridyl)benzene) (3)] with selected model proteins
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
Since the discovery of its therapeutic power in 1965, cisplatin has become the chemotherapeutic agent of choice for the treatment of different types of cancers, e.g., testicular, ovarian and bladder cancer, melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lymphomas and myelomas [1,2]
Summary
Since the discovery of its therapeutic power in 1965, cisplatin has become the chemotherapeutic agent of choice for the treatment of different types of cancers, e.g., testicular, ovarian and bladder cancer, melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lymphomas and myelomas [1,2]. Cisplatin and related compounds are known to bind to several classes of proteins with different roles, including transporters, antioxidants, electron transfer proteins, DNA-repair proteins, as well as proteins/peptides used as model systems to characterize the reactivity of metallodrugs in vitro, but that are present in vivo [11] In this regard, studies on the interactions of cisplatin and its analogues with proteins are fundamental in determining the overall pharmacological and toxicological profile of platinum drugs [11]. The 4 phenyl-2,2 :6 ,2 -terpyridine ligand has been already investigated by some of us as a stabile tridentate conjugate ligand for the Pt(IV) centre and, behaving like an antenna, gathers the light to promote the photoreduction to the corresponding Pt(II) analogue [21,23] Despite these Pt(II) compounds did not show any intercalative properties towards the DNA, they turned out to be very cytotoxic in vitro against the A2780 ovarian cancer cell line [21]. The UV-vis spectra reached equilibrium after about 40 h, confirming the stability of the new complex formed
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