13 research outputs found

    Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides

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    We show that UVA irradiation (365 nm) of the Pt-IV complex trans,trans,trans-[(PtCl2)-Cl-IV(OH)(2)(dimethylamine) (isopropylamine)] (1), induces reduction to Pt-II photoproducts. For the mixed amine Pt-II complex, trans[(PtCl2)-Cl-II(isopropylamine)(methylamine)] (2), irradiation at 365 nm increases the rate and extent of hydrolysis, triggering the formation of diaqua species. Additionally, irradiation increases the extent of reaction of complex 2 with guanosine-5'-monophosphate and affords mainly the bis-adduct, while reactions with adenosine-5'-monophosphate and cytidine-5'-monophosphate give rise only to mono-nucleotide adducts. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 1 and 2, and their photophysical and photochemical properties. UVA-irradiation can contribute to enhanced cytotoxic effects of diamine platinum drugs with trans geometry

    Interactions between Anticancertrans-Platinum Compounds and Proteins: Crystal Structures and ESI-MS Spectra of Two Protein Adducts of trans-(Dimethylamino)(methylamino)dichloridoplatinum(II)

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    The adducts formed between trans- (dimethylamino)(methylamino)dichloridoplatinum(II), [t-PtCl2(dma)(ma)], and two model proteins, i.e., hen egg white lysozyme and bovine pancreatic ribonuclease, were independently characterized by X-ray crystallography and electrospray ionization mass spectrometry. In these adducts, the PtII center, upon chloride release, coordinates either to histidine or aspartic acid residues while both alkylamino ligands remain bound to the metal. Comparison with the cisplatin derivatives of the same proteins highlights for [t-PtCl2(dma)(ma)] a kind of biomolecular metalation remarkably different from that of cisplatin

    Cisplatin and its dibromido analogue: a comparison of chemical and biological profiles

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    The dibromido analogue of cisplatin, cis-PtBr2(NH3)2 (cisPtBr2 hereafter), has been prepared and characterised. Its solution behaviour in standard phosphate buffer, at pH 7.4, was investigated spectrophotometrically and found to reproduce quite closely that of cisplatin; indeed, progressive sequential release of the two halide ligands typically occurs as in the case of cisplatin, with a roughly similar kinetics. Afterward, patterns of reactivity toward model proteins and standard ctDNA were explored and the nature of the resulting interactions elucidated. The antiproliferative properties were then evaluated in four representative cancer cell lines, namely A549 (human lung cancer), HCT116 (human colon cancer), IGROV-1 (human ovarian cancer) and FLG 29.1 (human acute myeloid leukaemia). Cytotoxic properties in line with those of cisplatin were highlighted. From these studies an overall chemical and biological profile emerges for cisPtBr2 closely matching that of cisplatin; the few slight, but meaningful differences that were underscored might be advantageously exploited for clinical application

    XPA, XPC, and XPD Modulate Sensitivity in Gastric Cisplatin Resistance Cancer Cells

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    Cisplatin is an election drug widely used in clinic for the treatment of advanced gastric cancer. However, the heterogeneity of the gastric tumors and its resistance to the drugs, make in some cases the response very low and the prognosis unpredictable. In this manuscript we aim to find the molecular processes involved in cisplatin-induced apoptosis in two gastric cancer cell lines with different sensitivity to the treatment: AGS and MKN45. The apoptosis induction is higher in MKN45 than in AGS cells in response to CDDP. The intrinsic apoptotic pathway study revealed that MKN45 cells undergo degradation of Mcl-1 together with an increase of Bid and Bad levels, which results in sensitivity to CDDP. In addition, DNA repair NER pathway is impair in MKN45 cells due to low levels of XPC and the absence of translocation of XPA and XPD to the nucleus after stimuli. Altogether, these results suggest that NER and Bcl-2 protein family proteins are potential targets to improve the response to cisplatin treatment

    New Findings in the Signaling Pathways of cis and trans Platinum Iodido Complexes' Interaction with DNA of Cancer Cells

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    We have selected a series of aliphatic amine platinum compounds bearing chloride and/or iodide as the leaving groups. The complexes’ cytotoxicity and interaction with DNA indicated differences in the reactivity. Now, we are reporting on the analysis of their molecular mechanism of action on gastric cancer cells. Our data reveals differences between them. Chlorido drugs showed similar behavior to cisplatin; they both required p53 to induce apoptosis but only cis-ipa showed DNA damage requirement for apoptosis induction. On the contrary, cis and trans iodido induced cell death independent of p53 activity, and they induced cell death through Bid activation, so their toxicity could be enhanced in a combined treatment with novel Bcl-2 protein family inhibitors. We also report the structural features of the DNA adduct for one of the complexes by X-ray diffraction. These findings represent a step forward in the search for new platinum-derived agents more specific and effective in the treatment of cancer.Authors A.G.Q., M.C., and A.A.-V. received funding from MINECO CTQ2015-68779-R. I.S.P. received funding from P17-01401 (supported by FEDER funds) from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, SpainNPL is a fellow of the Programa de Doctorado Biociencias Moleculares UAM, Madrid, Spain. NPL was supported by a fellowship Programa de Formación de Profesorado Universitario REF: FPU15/04669

    Reactions of a tetranuclear Pt-thiosemicarbazone complex with model proteins

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    The tetranuclear Pt complex (PtL)4 (where L2- is the anion derived from para-isopropyl thiosemicarbazone) was first described in A.G. Quiroga et al., J. Med. Chem. 41, 1998, 1399-1408. (PtL)4 manifests antiproliferative properties toward various cancer cell lines being a promising anticancer drug candidate. Yet, details of its reactivity with biomolecules have not been elucidated. To this end, we investigated the reactions of (PtL)4 with a few model proteins, i.e. bovine pancreatic ribonuclease (RNase A), cytochrome c (Cyt c) and hen egg white lysozyme (Lysozyme), through electrospray ionization mass spectrometry and other biophysical methods. A rich reactivity of (PtL)4 with the above-mentioned model proteins is observed, leading to the formation of numerous metallodrug-protein adducts. The tetranuclear complex breaks down and various fragments bind proteins up to high metal/protein ratios; this typically results into very complicated mass spectral patterns. However, some of the main mass peaks could be assigned in the case of the Lysozyme adduct. In addition, crystallographic data were obtained for the (PtL)4/Lysozyme and (PtL)4/RNase A adducts pointing at His side chains as the primary binding sites for monometallic Pt fragments. Notably, a few selected features of the interactions observed in the (PtL)4/protein adducts were reproduced by reacting (PtL)4 with a small molecule, i.e. N-methylimidazole. In conclusion, the present study confirms the prodrug nature of the tetraplatinum complex, clarifies one possible pathway for its activation through cluster disassembly and allows initial identification of adducts formed with a representative protein

    Versatile Route to trans-Platinum(II) Complexes via Manipulation of a Coordinated 3-(Pyridin-3-yl)propanoicAcid Ligand

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    We describe the direct coupling of alcohols and amines to a 3-(pyridin-3-yl)propanoic acid ligand coordinated to a Pt(II) to afford ester and amide derivatives. Using this approach, a family of trans-Pt(II) compounds with amine ligands bearing long perfluorinated chains was prepared, as these chains potentially endow the complexes with thermoactivatable properties. Related compounds with alkyl chains in place of the perfluorinated chains were also prepared as controls using the same direct coupling method. The stability of the complexes in solution, their reactivity with DNA and proteins, and their antiproliferative activity evaluated in tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK293) cells at 37 degrees C and following exposure to elevated temperatures (that mimic the temperatures employed in thermotherapy) were also studied to assess their utility as putative (thermoactivated) anticancer agents

    Two different thiosemicarbazone tauto-conformers coordinate to Palladium (II): Stability and biological studies of the final complexes

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    Thiosemicarbazone moiety is a valuable scaffold for the synthesis of metallic complexes with anticancer purposes, when bearing N-heterocyclic the final compounds possess diverse biological activities. Using thiazole as bioisosteres, the resulting thiosemicarbazones can afford synthetic drugs with a variety of pharmacological effects. Trying to elucidate, if metal complexes from α-N-heterocyclic thiosemicarbazones can achieve more selectivity versus special tumor lines, we have developed new metal complexes with 1H imidazole-4-carboxaldehyde 4 N-ptolyl- and 4 N-phenylthiosemicarbazone (HL1 and HL2 respectively). The solution studies of these ligands showed a tautomeric equilibria in solution and their reaction with Li2PdCl4 proved the stability of both forms affording two mononuclear Pd(II) complexes. Both tautomeric forms are clearly coordinated to palladium center acting as two different bidentate ligands. Palladium complexes’ stability in biological buffers was investigated to stablish the optimal conditions for the evaluation of cytotoxicity, that on the triple negative adenocarcinoma cell line showed IC50 values in the low micromolar range. Complexes were also studied with CT DNA (UV-Visible spectroscopy and viscosity) and with the pBR322 plasmid supercoiled models, indicating non covalent interaction.Fil: Fabra, David. Universidad Autónoma de Madrid; EspañaFil: Matesanz, Ana I.. Universidad Autónoma de Madrid; EspañaFil: Herrero, Jorge M.. Universidad Autónoma de Madrid; EspañaFil: Alvarez, Cristina. Universidad Autónoma de Madrid; EspañaFil: Balsa, Lucia Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Leon, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Quiroga, Adoracion G.. Universidad Autónoma de Madrid; Españ

    Peculiar Features in the Crystal Structure of the Adduct Formed between <i>cis</i>-PtI<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub> and Hen Egg White Lysozyme

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    The reactivity of <i>cis</i>-diamminediiodidoplatinum­(II), <i>cis</i>-PtI<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub>, 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<sup>II</sup> 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<sup>II</sup> 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

    Interactions between Anticancer <i>trans</i>-Platinum Compounds and Proteins: Crystal Structures and ESI-MS Spectra of Two Protein Adducts of <i>trans</i>-(Dimethylamino)(methylamino)dichloridoplatinum(II)

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    The adducts formed between <i>trans</i>-(dimethylamino)­(methylamino)­dichloridoplatinum­(II), [t-PtCl<sub>2</sub>(dma)­(ma)], and two model proteins, i.e., hen egg white lysozyme and bovine pancreatic ribonuclease, were independently characterized by X-ray crystallography and electrospray ionization mass spectrometry. In these adducts, the Pt<sup>II</sup> center, upon chloride release, coordinates either to histidine or aspartic acid residues while both alkylamino ligands remain bound to the metal. Comparison with the cisplatin derivatives of the same proteins highlights for [t-PtCl<sub>2</sub>(dma)­(ma)] a kind of biomolecular metalation remarkably different from that of cisplatin
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