Reaction with Proteins of a Five-Coordinate Platinum(II) Compound (original) (raw)
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International Journal of Molecular Sciences, 2021
Three novel platinum(II) complexes bearing N-heterocyclic ligands, i.e., Pt2c, Pt-IV and Pt-VIII, were previously prepared and characterized. They manifested promising in vitro anticancer properties associated with non-conventional modes of action. To gain further mechanistic insight, we have explored here the reactions of these Pt compounds with a few model proteins, i.e., hen egg white lysozyme (HEWL), bovine pancreatic ribonuclease (RNase A), horse heart cytochrome c (Cyt-c) and human serum albumin (HSA), primarily through ESI MS analysis. Characteristic and variegate patterns of reactivity were highlighted in the various cases that appear to depend both on the nature of the Pt complex and of the interacting protein. The protein-bound Pt fragments were identified. In the case of the complex Pt2c, the adducts formed upon reaction with HEWL and RNase A were further characterized by solving the respective crystal structures: this allowed us to determine the exact location of the var...
Inorganic Chemistry, 2013
A B S T R A C T : T h e r e a c t i v i t y o f c i sdiamminediiodidoplatinum(II), cis-PtI 2 (NH 3 ) 2 , the iodo analogue of cisplatin, with hen egg white lysozyme (HEWL) was investigated by electrospray ionization mass spectrometry and X-ray crystallography. Interestingly, the study compound forms a stable 1:1 protein adduct for which the crystal structure was solved at 1.99 Å resolution. In this adduct, the Pt II center, upon release of one ammonia ligand, selectively coordinates to the imidazole of His15. Both iodide ligands remain bound to platinum, with this being a highly peculiar and unexpected feature. Notably, two equivalent modes of Pt II binding are possible that differ only in the location of I atoms with respect to ND1 of His15. The structure of the adduct was compared with that of HEWL−cisplatin, previously described; differences are stressed and their important mechanistic implications discussed. C isplatin [cis-diamminedichloroplatinum(II)] is a leading anticancer drug in widespread clinical use for the treatment of several types of malignancies. 1 Since the discovery of cisplatin, research has been largely focused on the characterization of platinum−DNA adducts according to the concept that DNA is its primary biological target: these studies indicated the N7 atom of guanine as the preferential platination site. 2 Interestingly, bifunctional adducts involving two adjacent nucleobases are predominantly formed by cisplatin 3 that are believed to represent the major DNA lesions, ultimately leading to apoptotic cancer cell death. Yet, nucleobases are not the only biological targets for platinum drugs. Cys, Met, and His residues in proteins are alternative reactive sites to which platinum can efficiently coordinate. 4 The interaction between cisplatin and proteins is underscored by a number of crystallographic and electrospray ionization mass spectrometry (ESI MS) studies that include determination of the complexes between this molecule and hen egg white lysozyme (HEWL), 5 transferrin, 6 the copper chaperone Atox-1, 7 hemoglobin, 8 cytochrome c, 9 ubiquitin, 10 DNA polymerase, 11 metallothionein, 12 and superoxide dismutase. 13 In 2007, Casini et al. determined the X-ray structure of the HEWL−cisplatin derivative obtained by soaking experiments on pregrown HEWL crystals, at 1.9 Å resolution. The structure revealed selective platination of the only HEWL histidine residue, i.e., His15, at the imidazole ND1 atom (at the so-called righthanded site). 5a Pt II has an occupancy equal to 0.3 and is also bound to the N atoms of two ammonia molecules. The fourth ligand was not detected ( in the Supporting Information, SI). This result was in substantial agreement with the ESI MS spectra of HEWL−cisplatin derivatives, which showed two peaks of similar intensity at 14569 and 14605 Da, formally corresponding to either a [Pt(NH 3 ) 2 Cl] + fragment or intact cisplatin bound to HEWL. A similar situation was described by Dyson and co-workers in the case of the cisplatin−transferrin system and interpreted in terms of a two-step cisplatin-to-protein binding process. More recently, cocrystallization experiments conducted by Helliwell and co-workers revealed that cisplatin binds HEWL by coordinating either the ND1 or the NE2 atom (i.e., it can bind at the so-called "right-handed" and "left-handed" sites) of the imidazole ring of His15, 5b,c after release of one chlorine ligand ( in the SI).
Thermodynamic Evaluation of the Interactions between Anticancer Pt(II) Complexes and Model Proteins
Molecules
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-spec...
Inorganic Chemistry, 2012
Six diiodido−diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.
Inorganica Chimica Acta, 2002
Square-planar [PtX 2 (Me 2 PHEN)] complexes (Me 2 PHEN 0/2,9-dimethyl-1,10-phenanthroline) behave as a spring trap and react with an extra ligand (L) to give the addition product [PtX 2 (L)(Me 2 PHEN)] in which the Me 2 PHEN plane is perpendicular to the coordination plane of the other three ligands. For X 0/I and L0/PY or APY (PY, pyridine, APY, 2-amino-pyridine) the addition product has monocoordinated Me 2 PHEN. The free and coordinated ends of Me 2 PHEN are in rapid exchange at room temperature but the exchange becomes slow, in the NMR time scale, at low temperature (213 K). In chloroform solution and at room temperature, the addition product is indefinitely stable in the case of PY while in the case of APY displacement of a iodo ligand by the free end of Me 2 PHEN and formation of the cationic species [PtI(L)(Me 2 PHEN)]I take place in a few hours. An anchimeric assistance of the exocyclic aminic-group of APY in the release of the iodide ion is suggested. The displacement of the iodide is also favored by solvents of higher solvating ability and/or dielectric constants such as methanol. The single crystal X-ray structures of [PtI(APY)(Me 2 PHEN)]I ×/2CHCl 3 (1 ×/2CHCl 3 ) and [PtI(MeCY)(Me 2 PHEN)]I ×/CH 3 OH (2 ×/CH 3 OH) (MeCY, 1-methyl-cytosine) have revealed that the steric repulsion towards cis -ligands is smaller for the APY and MeCY ligands than for I and that chloroform can give intermolecular interactions with the phenanthroline moiety which can compete with stacking interactions between phenanthroline ligands. #