Thermodynamic Evaluation of the Interactions between Anticancer Pt(II) Complexes and Model Proteins (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...
Reaction with Proteins of a Five-Coordinate Platinum(II) Compound
International Journal of Molecular Sciences, 2019
Stable five-coordinate Pt(II) complexes have been highlighted as a promising and original platform for the development of new cytotoxic drugs. Their interaction with proteins has been scarcely studied. Here, the reactivity of the five-coordinate Pt(II) compound [Pt(I)(Me) (dmphen)(olefin)] (Me = methyl, dmphen = 2,9-dimethyl-1,10-phenanthroline, olefin = dimethylfumarate) with the model proteins hen egg white lysozyme (HEWL) and bovine pancreatic ribonuclease (RNase A) has been investigated by X-ray crystallography and electrospray ionization mass spectrometry. The X-ray structures of the adducts of RNase A and HEWL with [Pt(I)(Me)(dmphen)(olefin)] are not of very high quality, but overall data indicate that, upon reaction with RNase A, the compound coordinates the side chain of His105 upon releasing the iodide ligand, but retains the pentacoordination. On the contrary, upon reaction with HEWL, the trigonal bi-pyramidal Pt geometry is lost, the iodide and the olefin ligands are rele...
Inorganic Chemistry, 2012
The interactions of two organoplatinum complexes, [Pt(C ∧ N)Cl(dppa)], 1, and [Pt(C ∧ N)Cl(dppm)], 2 (C ∧ N = N(1), C(2′)-chelated, deprotonated 2-phenylpyridine, dppa = bis(diphenylphosphino)amine, dppm = bis(diphenylphosphino)methane), as antitumor agents, with bovine serum albumin (BSA) and human serum albumin (HSA) have been studied by fluorescence and UV−vis absorption spectroscopic techniques at pH 7.40. The quenching constants and binding parameters (binding constants and number of binding sites) were determined by fluorescence quenching method. The obtained results revealed that there is a strong binding interaction between the ligands and proteins. The calculated thermodynamic parameters (ΔG, ΔH, and ΔS) confirmed that the binding reaction is mainly entropy-driven, and hydrophobic forces played a major role in the reaction. The displacement experiment shows that these Pt complexes can bind to the subdomain IIA (site I) of albumin. Moreover, synchronous fluorescence spectroscopy studies revealed some changes in the local polarity around the tryptophan residues. Finally, the distance, r, between donor (serum albumin) and acceptor (Pt complexes) was obtained according to Forster theory of nonradiation energy transfer.
Studies of interactions between platinum(II) complexes and some biologically relevant molecules
Bioorganic & Medicinal Chemistry, 2007
The reactions of Pt(II) complexes, cis-[Pt(NH 3 ) 2 Cl 2 ], [Pt(terpy)Cl] + , [Pt(terpy)(S-cys)] 2+ , and [Pt(terpy)(N7-guo)] 2+ , where terpy = 2,2 0 :6 0 ,2 00 -terpyridine, S-cys = L L-cysteine, and N7-guo = guanosine, with some biologically relevant ligands such as guanosine-5 0 -monophosphate (5 0 -GMP), L L-cysteine, glutathione (GSH) and some strong sulfur-containing nucleophiles such as diethyldithiocarbamate (dedtc), thiosulfate (sts), and thiourea (tu), were studied in aqueous 0.1 M Hepes at pH of 7.4 using UV-vis, stopped-flow spectrophotometry, and 1 H NMR spectroscopy.
The development of resistance and unwanted harmful interaction with other biomolecules instead of DNA are the major drawbacks for application of platinum (Pt) complexes in cancer chemotherapy. To conquer these problems, much works have been done so far to discover innovative Pt complexes. The objective of the current study was to evaluate the anti cancer activities of a series of four and five-coordinated Pt(II) complexes, having deprotonated 2-phenyl pyridine (abbreviated as C^N), biphosphine moieties, i.e., dppm 0bis(diphenylphosphino) methane (Ph 2 PCH 2 PPh 2 ) and dppa 0bis(diphenylphosphino)amine (Ph 2 PNHPPh 2 ), as the non-leaving carrier groups. The growth inhibitory effect of the Pt complexes [Pt(C^N)(dppm)]PF 6 : C 1 , [Pt(C^N)(dppa)]PF 6 : C 2 , and [Pt(C^N)I (dppa)]: C 3 , toward the cancer cell lines was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. In addition, the florescence quenching experiments of the interaction between human serum albumin (HSA) and the Pt complexes were performed in order to obtain the binding parameters and to evaluate the denaturing properties of these complexes upon binding to the general carrier protein of blood stream. The structure-activity relationship studies reveal that four-coordinated Pt complexes C 1 and C 2 with both significant hydrophobic and charge characteristics, not only exhibit strong antiproliferation activity toward the cancer cell lines, but also they display lower denaturing effect against carrier protein HSA. On the other hand, five-coordinated C 3 complex with the unusual intermolecular NH…Pt hydrogen binding and the intrinsic ability for oligomerization, exhibits poor anticancer activity and strong denaturing property. The current study reveals that the balance between charge and hydrophobicity of the Pt complexes, also their hydrogen binding abilities and coordination mode are important for their anticancer activities. Moreover, this study may suggest C 1 and C 2 as the potential template structures for synthesis of new generation of four-coordinated Pt complexes with strong anticancer activities and weak denaturing effects against proteins.
Anticancer activity and DNA-binding properties of novel cationic Pt(II) complexes
International Journal of Biological Macromolecules, 2014
In this study, three structurally related cationic Pt complexes, [Pt(ppy)(dppe)]CF 3 CO 2 : C 1 , [Pt(bhq)(dppe)]CF 3 CO 2 : C 2 , and [Pt(bhq)(dppf)]CF 3 CO 2 : C 3 , in which ppy = deprotonated 2phenylpyridine, bhq = deprotonated benzo[h]quinoline, dppe = bis(diphenylphosphino)ethane and dppf = 1,1-bis(diphenylphosphino)ferrocene, were used for the assessment of their anticancer activities against Jurkat and MCF-7 cancer cell lines. The Pt complexes (C 1-C 3) demonstrated significant level of anticancer properties, as measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Moreover, the changes in nuclear morphology with Acridine Orange (AO) staining reveal that these complexes are capable to induce apoptosis, and only C 1 stimulates activity of Caspase-3 in Jurkat cancer cells. To get a better insight into the nature of binding between these cationic Pt complexes and DNA, different spectroscopic techniques and gel electrophoresis were applied. On the basis of the results of UV/vis absorption spectroscopy, CD experiment and fluorescence quenching of ethidium bromide (EB)-DNA, the interaction between DNA and the Pt complexes is likely to occur through a mixed-binding mode. Overall, the present work suggests that a controlled modification could result in new potentially antitumor complexes which can survive the repair mechanism and induce facile apoptosis.