- In vitro and in vivoactivity of series of cationic dinuclearPt(II) complexes
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The antitumour potential of nine dinuclear platinum(II) complexes of the type [{Pt(L)Cl}2(μ-X)]2+(where L represents two NH3 or different bidentantly coordinated diamine ligand - ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach; 1,3-propylenediamine, 1,3-pd; 2,2-dimethyl-1,3-propylenediamine, 2,2-diMe-1,3-pd; (±)-1,3-pentanediamine,1,3-pnd, and X is a bridging pyrazine (pz) or pyridazine (pydz) ligand) were determined by in vitro and in vivo assays using the CT26 cell line and a murine model of heterotopic colon cancer tumour induced in immunocompetent BALB/c mice. This study concludes that complexes Pt1, Pt2 and Pt7 possess significant in vitro cytotoxic activity against mouse colon carcinoma CT26 cells, while all these complexes show moderate apoptotic effect. Complexes Pt1 and Pt7 arrested CT26 cells in G2/M phase of cell cycle, while, evaluated by detection of Ki67 expressing cells, complexes Pt5 and Pt6 exerted the highest antiproliferative effect. Complexes Pt1 and Pt2 exerted significant in vivo antitumour effects. These complexes reduced the growth of primary tumour and the incidence of lung and liver metastases without causing the significant hepato- and nephro- toxicity. Our data indicate considerable antitumour activity of platinum(II) complexes against CT26 cells in vitro and in vivo and imply possible further investigations on their role as potential chemotherapeutic agents.
- Vasi?, Ivana,Rajkovi?, Sne?ana,Arsenijevi?, Aleksandar,Milovanovi?, Marija,Arsenijevi?, Neboj?a,Milovanovi?, Jelena,?ivkovi?, Marija D.
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- Nucleolar Stress Induction by Oxaliplatin and Derivatives
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Platinum(II) compounds are a critical class of chemotherapeutic agents. Recent studies have highlighted the ability of a subset of Pt(II) compounds, including oxaliplatin but not cisplatin, to induce cytotoxicity via nucleolar stress rather than a canonical DNA damage response. In this study, influential properties of Pt(II) compounds were investigated using redistribution of nucleophosmin (NPM1) as a marker of nucleolar stress. NPM1 assays were coupled to calculated and measured properties such as compound size and hydrophobicity. The oxalate leaving group of oxaliplatin is not required for NPM1 redistribution. Interestingly, although changes in diaminocyclohexane (DACH) ligand ring size and aromaticity can be tolerated, ring orientation appears important for stress induction. The specificity of ligand requirements provides insight into the striking ability of only certain Pt(II) compounds to activate nucleolar processes.
- Sutton, Emily C.,Mcdevitt, Christine E.,Prochnau, Jack Y.,Yglesias, Matthew V.,Mroz, Austin M.,Yang, Min Chieh,Cunningham, Rachael M.,Hendon, Christopher H.,Derose, Victoria J.
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supporting information
p. 18411 - 18415
(2019/11/19)
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- Synthesis, cytotoxic activity and DNA interaction studies of new dinuclear platinum(ii) complexes with an aromatic 1,5-naphthyridine bridging ligand: DNA binding mode of polynuclear platinum(ii) complexes in relation to the complex structure
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The synthesis, spectroscopic characterization, cytotoxic activity and DNA binding evaluation of seven new dinuclear platinum(ii) complexes Pt1-Pt7, with the general formula [{Pt(L)Cl}2(μ-1,5-nphe)](ClO4)2 (1,5-nphe is 1,5-naphthyridine; while L is two ammines (Pt1) or one bidentate coordinated diamine: ethylenediamine (Pt2), (±)-1,2-propylenediamine (Pt3), trans-(±)-1,2-diaminocyclohexane (Pt4), 1,3-propylenediamine (Pt5), 2,2-dimethyl-1,3-propylenediamine (Pt6), and 1,3-pentanediamine (Pt7)), were reported. In vitro cytotoxic activity of these complexes was evaluated against three tumor cell lines, murine colon carcinoma (CT26), murine mammary carcinoma (4T1) and murine lung cancer (LLC1) and two normal cell lines, murine mesenchymal stem cells (MSC) and human fibroblast (MRC-5) cells. The results of the MTT assay indicate that all investigated complexes have almost no cytotoxic effects on 4T1 and very low cytotoxicity toward LLC1 cell lines. In contrast to the effects on LLC1 and 4T1 cells, complexes Pt1 and Pt2 had significant cytotoxic activity toward CT26 cells. Complex Pt1 had a much lower IC50 value for activity on CT26 cells compared with cisplatin. In comparison with cisplatin, all dinuclear Pt1-Pt7 complexes showed lower cytotoxicity toward normal MSC and MRC-5 cells. In order to measure the amount of platinum(ii) complexes taken up by the cells, we quantified the cellular platinum content using inductively coupled plasma mass spectrometry (ICP-QMS). Molecular docking studies performed to evaluate the potential binding mode of dinuclear platinum(ii) complexes Pt1-Pt7 and their aqua derivatives W1-W7, respectively, at the double stranded DNA showed that groove spanning and backbone tracking are the most stable binding modes.
- Konovalov, Bata,?ivkovi?, Marija D.,Milovanovi?, Jelena Z.,Djordjevi?, Dragana B.,Arsenijevi?, Aleksandar N.,Vasi?, Ivana R.,Janji?, Goran V.,Franich, Andjela,Manojlovi?, Dragan,Skrivanj, Sandra,Milovanovi?, Marija Z.,Djuran, Milo? I.,Rajkovi?, Sne?ana
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p. 15091 - 15102
(2018/11/10)
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- Synthesis of different pyrazine-bridged platinum(II) complexes and 1H NMR study of their catalytic abilities in the hydrolysis of the N-acetylated l-methionylglycine
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Four binuclear {[Pt(L)Cl]2(μ-pz)}Cl2-type complexes have been synthesized and characterized by elemental microanalyses and NMR (1H and 13C) spectroscopy (L is ethylenediamine, en; (±)-1,2-propylenediamine, 1,2-pn; isobutylenediamine, ibn; trans-(±)-1,2-diaminocyclohexane, dach and pz is bridging pyrazine ligand). The chlorido complexes were converted into the corresponding aqua species, {[Pt(L)(H2O)]2(μ-pz)}4+, and 1H NMR spectroscopy was applied to study their reactions with the N-acetylated l-methionylglycine, Ac-L-Met-Gly. The {[Pt(L)(H2O)] 2(μ-pz)}4+ complex and dipeptide were reacted in 1:1 and 1:2 M ratios, respectively, and all reactions were performed in the pH range 2.0-2.5 and at 37 C. In the reactions with equimolar amounts of the reactants all Pt(II) aqua complexes bind to the methionine side chain of Ac-L-Met-Gly dipeptide and promote the cleavage of the amide bond involving the carboxylic group of methionine. It was found that the amount of hydrolyzed dipeptide strongly depends from the steric bulk of bidentate coordinated diamine ligand L in {[Pt(L)(H2O)]2(μ-pz)}4+ complex (en > 1,2-pn > ibn > dach). However, in the reaction with an excess of dipeptide the influence of the nature of diamine ligand L on this hydrolytic process could not be observed due to the fact that slow decomposition of {[Pt(L)(H 2O)]2(μ-pz)}4+ complex was occured.
- Rajkovi?, Sne?ana,A?anin, Darko P.,?ivkovi?, Marija D.,Djuran, Milo? I.
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- Hydrolysis of the amide bond in N-acetylated l-methionylglycine catalyzed by various platinum(II) complexes under physiologically relevant conditions
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The hydrolytic reactions between various Pt(II) complexes of the type [Pt(L)Cl2] and [Pt(L)(CBDCA-O,O′] (L is ethylenediamine, en; (±)-trans-1,2-diaminocyclohexane, dach; (±)-1,2-propylenediamine, 1,2-pn and CBDCA is the 1,1-cyclobutanedicarboxylic anion) and the N-acetylated l-methionylglycine dipeptide (MeCOMet-Gly) were studied by 1H NMR spectroscopy. All reactions were realized at 37 °C with equimolar amounts of the Pt(II) complex and the dipeptide at pH 7.40 in 50 mM phosphate buffer in D2O. Under these experimental conditions, a very slow cleavage of the Met-Gly amide bond was observed and this hydrolytic reaction proceeds through the intermediate [Pt(L)(H2O)(MeCOMet-Gly-S)]+ complex. In general, it can be concluded that faster hydrolytic cleavage of the MeCOMet-Gly dipeptide was observed in the reaction with the chloride complex than with corresponding CBDCA Pt(II) complexes. The steric effects of the Pt(II) complex on the hydrolytic cleavage of the amide bond in the MeCOMet-Gly dipeptide were also investigated by 1H NMR spectroscopy. It was found that the rate of hydrolysis decreases as the steric bulk of the CBDCA and chlorido Pt(II) complexes increase (en > 1,2-pn > dach). These results contribute to a better understanding of the toxic side effects of Pt(II) antitumor drugs and should be taken into consideration when designing new potential Pt(II) antitumor drugs with preferably low toxic side effects.
- ?ivkovi?, Marija D.,A?anin, Darko P.,Rajkovi?, Sne?ana,Djuran, Milo? I.
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p. 947 - 952
(2011/05/04)
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- Trend in cytotoxic activity of a series of cis-[APtCl2] (A = ethylenediamine methylated at different positions) complexes
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The study of a series of cis-[APtCl2] complexes (A = ethylenediamine, en, methylated at different positions) was carried out to evaluate the effect of different methyl substitutions on the cytotoxic properties of the resulting derivatives. As expected, differentially methylated complexes were found to differ widely in their cytotoxic effects on human cultured ovarian carcinoma cells (A2780). Molecular mechanics (MM) calculations have been performed to assess the relationship between differential diamine methylation and the repulsive energy of the corresponding complexes when interacting with DNA. Compounds that bind DNA at high energetic cost relative to cisplatin, due to the steric hindrance of additional methyl groups, have shown high values for IC50 (concentration inhibiting tumour cell growth by 50%). Semi-quantitative analyses with a DNA electrochemical biosensor confirm that the interaction between cis-[APtCl2] complexes and ds-DNA deposed onto the electrode is stronger for the non-methylated derivative with respect to the fully methylated congener. In addition, MM calculations were used to investigate the interactions between DNA and cis-[(P-L-A)PtCl2] complexes [A = en group linked to an antiestrogen-like pharmacophore, P, via a -(CH2)n- spacer (n = 2, 4, 6, 8 and 10), L].
- Milanesio, Marco,Monti, Elena,Gariboldi, Marzia Bruna,Gabano, Elisabetta,Ravera, Mauro,Osella, Domenico
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p. 2803 - 2814
(2009/02/03)
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- Atom-transfer and outer-sphere reductions of platinum(IV) complexes. A comparative kinetic investigation
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Reductions of platinum(IV) complexes of the type (N-N=en, meen, dmen, tmen, 1,2-pn, 1,3-pn) by FeCp2, Bu4NI and (ClO4)2 in the presence of Et4NCl have been kinetically investigated in methanol solution.The reactions with FeCp2 or Bu4NI obey e second-order rate law reductant), whereas the rate law for the reactions with (ClO4)2 in the presence of Et4NCl is: rate = Pt(II)+kPt(II)->2+4>.The reactivity of the complexes is enhanced by an increased steric hindrance of the N-N ligand.Such a reactivity trend is likely to be related to a parallel increased thermodynamic tendency of platinum(IV) towards reduction.The effect of steric hindrance on the rate is less pronounced in the reaction with 2+ probably due to a direct interaction between the N-N and the NH2Et ligands in the activated complex
- Peloso, Arnaldo,Mohamud, Sacid Issa
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p. 349 - 354
(2007/10/02)
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