- Chromatin Regulates Genome Targeting with Cisplatin
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Cisplatin derivatives can form various types of DNA lesions (DNA-Pt) and trigger pleiotropic DNA damage responses. Here, we report a strategy to visualize DNA-Pt with high resolution, taking advantage of a novel azide-containing derivative of cisplatin we named APPA, a cellular pre-extraction protocol and the labeling of DNA-Pt by means of click chemistry in cells. Our investigation revealed that pretreating cells with the histone deacetylase (HDAC) inhibitor SAHA led to detectable clusters of DNA-Pt that colocalized with the ubiquitin ligase RAD18 and the replication protein PCNA. Consistent with activation of translesion synthesis (TLS) under these conditions, SAHA and cisplatin cotreatment promoted focal accumulation of the low-fidelity polymerase Polη that also colocalized with PCNA. Remarkably, these cotreatments synergistically triggered mono-ubiquitination of PCNA and apoptosis in a RAD18-dependent manner. Our data provide evidence for a role of chromatin in regulating genome targeting with cisplatin derivatives and associated cellular responses.
- Zacharioudakis, Emmanouil,Agarwal, Poonam,Bartoli, Alexandra,Abell, Nathan,Kunalingam, Lavaniya,Bergoglio, Valérie,Xhemalce, Blerta,Miller, Kyle M.,Rodriguez, Rapha?l
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- An unexpected in-solution instability of diiodido analogue of picoplatin complicates its biological characterization
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Complex cis-[PtI2(NH3)(pic)] (1; pic = 2-methylpyridine), a diiodido analogue of clinically studied picoplatin (2), is unstable in solution, which is intriguingly connected with the release of its pic ligand. This observation complicates the biological testing of e.g. cytotoxicity in human cancer cells for 1.
- ?tarha, Pavel,Draho?, Bohuslav,Herchel, Radovan
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- VISUAL DETECTION OF PLATINATED DNA LESIONS FROM A CLICKABLE CISPLATIN PROBE USED AS DIAGNOSTIC TOOL OR TO IDENTIFY SYNERGISTIC TREATMENTS
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The present invention relates to a new compound for visualizing DNA-platinum crosslink, and its use as a research tool and in screening method for identifying candidate drug to be used in combination with platinating compounds such as cisplatin, carboplatin, and oxaliplatin. Formulae (I), (II) or (III). The project leading to this application has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No [647973]).
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- IMPROVEMENTS IN PLATINUM COMPOUNDS PREPARATION BY USE OF TETRABUTYLAMMOUNIUM AMMINETRICHLOROPLATINATE AS INTERMEDIATE
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The invention provides a commercially practicable route to X[PtCl 3 (NH 3 )], where X represents an alkali metal ion, comprising the steps of heating a reaction mixture comprising cisplatin in an acidified organic solvent, together with NBu 4 OH, a Pt catalyst and saturated aqueous NaC1 solution to form (NBu 4 )[PtCl 3 (NH 3 )], and reacting that product with an alkali metal salt, to form X[PtCl 3 (NH 3 )] The product may be used in the synthesis of platinum anticancer complexes.
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Page/Page column 4
(2010/01/07)
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- Photoactive trans ammine/amine diazido platinum(IV) complexes
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The synthesis and characterisation of eight new octahedral PtIV complexes of the type trans,trans,trans-[Pt(N3)2(OH)2(NH3)(Am)] where Am = methylamine (2), ethylamine (4), thiazole (6), 2-picoline (8)
- Mackay, Fiona S.,Moggach, Stephen A.,Collins, Anna,Parsons, Simon,Sadler, Peter J.
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p. 811 - 819
(2009/05/30)
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- Platinum(IV) analogues of AMD473 (cis-[PtCl2(NH 3)(2-picoline)]): Preparative, structural, and electrochemical studies
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The preparation and oxidation of the anticancer drug AMD473, cis-[PtCl 2(NH3)(2-pic)] (2-pic = 2-methylpyridine), has been investigated. cis-[PtCl2(NH3)(2-pic)] is readily oxidized with peroxide to give the trans-dihydroxoplatinum-(IV) complex cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)]. The crystal structure of this complex reveals that it is highly strained as a result of a steric clash between the methyl group of the 2-picoline ligand and an axial hydroxo ligand, with the Pt-N-C angle adjacent to this clash opened up to an unprecedented 138.6(6)°. Attempts at converting the dihydroxoplatinum(IV) complex to dichloro and diacetato analogues were unsuccessful with reaction with HCl leading to loss and protonation of the 2-picoline ligand to form the salt (2-picH)[PtCl5(NH3)] and the platinum(II) complex cis-[PtCl2(NH3)(2-pic)], both confirmed by crystallography. Electrochemical studies revealed that cis,trans,-cis-[PtCl 2(OH)2(NH3)(2-pic)] is reduced more readily (-714 mV vs Ag/AgCl) than its pyridine analogue cis,trans,-cis-[PtCl 2(OH)2(NH3)(pyridine)] (-770 mV vs Ag/AgCl) consistent with the steric clash in the former complex destabilizing the platinum(IV) oxidation state.
- Battle, Andrew R.,Choi, Robin,Hibbs, David E.,Hambley, Trevor W.
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p. 6317 - 6322
(2008/10/09)
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- Contrasting chemistry of cis- and trans-platinum(II) diamine anticancer compounds: Hydrolysis studies of picoline complexes
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cis-[PtCl2(NH3)(2-picoline)] (AMD473) is currently on clinical trials as an anticancer drug. The trans isomer, AMD443 (1), is also cytotoxic in a variety of cancer cell lines. The X-ray crystal structure of the trans isomer (1) shows that the pyridine ring is tilted by 69° with respect to the platinum square-plane in contrast to the cis isomer in which it is almost perpendicular (103°). In the 3-picoline (2) and 4-picoline (3) trans isomers, the ring is tilted by 58°/60° (2 molecules/unit cell) and by 56°, respectively. Hydrolysis may be an important step in the intracellular activation and anticancer mechanism of action of these complexes. The first hydrolysis step is relatively fast even at 277 K, with rate constants (determined by 1H, 15N NMR) of k1 = 2.6 × 10-5 s-1, 12.7 × 10-5 s-1, and 5.2 × 10-5 s-1 (l = 0.1 M) for formation of the monoaqua complexes of 1-3, respectively. Although the hydrolysis of 3 is slower than 2, it is hydrolyzed to a greater extent. No formation of the diaqua complex was observed for any of the three complexes at 277 K, and it accounts for a values for the monoaqua adducts of 1-3 were determined to be 5.55, 5.35, and 5.39, respectively, suggesting that they would exist largely as the monohydroxo complex at physiological pH. The pKa values for the diaqua adducts were determined to be 4.03 and 7.01 for 1, 3.97 and 6.78 for 2, and 3.94 and 6.88 for 3, the first pKa being >1 unit lower than for related cis complexes.
- McGowan, Geraldine,Parsons, Simon,Sadler, Peter J.
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p. 7459 - 7467
(2008/10/09)
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