15663-27-1Relevant articles and documents
Copper-free click-chemistry platform to functionalize cisplatin prodrugs
Pathak, Rakesh K.,McNitt, Christopher D.,Popik, Vladimir V.,Dhar, Shanta
, p. 6861 - 6865 (2014)
The ability to rationally design and construct a platform technology to develop new platinum(IV) [PtIV] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well-defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of PtIV centers, we used a strain-promoted azide-alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single PtIV precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated.
Glassy carbon electrodes deliver unpredictable reduction potentials for platinum(IV) antitumor prodrugs
McCormick, Meghan C.,Schultz, Franklin A.,Baik, Mu-Hyun
, p. 28 - 34 (2016)
Reductive activation of six-coordinate Pt(IV) complexes to afford square-planar Pt(II) complexes has exhibited surprisingly divergent and unpredictable cathodic peak potentials during cyclic voltammetry (CV) measurements under widely employed experimental conditions. A systematic, detailed investigation reveals that glassy carbon (GC) electrodes are responsible for this erratic behavior. More reproducible CVs are obtained with platinum metal electrodes, which display cathodic responses at much more positive potentials. The unreliable and negatively shifted peak potentials observed at GC are attributed to a non-uniform oxide layer that is formed on the electrode surface causing slow electron transfer. A simple procedure of repetitive scanning to reducing potentials is found to be effective for cleaning and activating the GC surface, such that it exhibits the more consistent and accurate peak potential responses seen with a Pt electrode.
Kinetic characterization of the interactions of trans-dichloro-platinum(IV) anticancer prodrugs and a model compound with thiosulfate
Dong, Jingran,Huo, Shuying,Song, Changying,Shen, Shigang,Ren, Yanli,Shi, Tiesheng
, p. 127 - 133 (2014)
Sodium thiosulfate has been utilized as a rescuing agent for relief of the toxic effects of cisplatin and carboplatin. In this work, we characterized the kinetics of reactions of the trans-dichloro-platinum(IV) complexes cis-[Pt(NH3)2Cl4], ormaplatin [Pt(dach)Cl 4] and trans-[PtCl2(CN)4]2- (anticancer prodrugs and a model compound) with thiosulfate at biologically important pH. An overall second-order rate law was established for the reduction of trans-[PtCl2(CN)4]2- by thiosulfate, and varying the pH from 4.45 to 7.90 had virtually no influence on the reaction rate. In the reactions of thiosulfate with cis-[Pt(NH3) 2Cl4] and with [Pt(dach)Cl4], the kinetic traces displayed a fast reduction step followed by a slow substitution involving the intermediate Pt(II) complexes. The reduction step also followed second-order kinetics. Reductions of cis-[Pt(NH3)2Cl 4] and [Pt(dach)Cl4] by thiosulfate proceeded with similar rates, presumably due to their similar configurations, whereas the reduction of trans-[PtCl2(CN)4]2- was about 1,000 times faster. A common reduction mechanism is suggested, and the transition state for the rate-determining step has been delineated. The activation parameters are consistent with transfer of Cl+ from the platinum(IV) center to the attacking thiosulfate in the rate-determining step.
Synthesis of pyrophosphatotetraamminediplatinum(II) complex and its transformations in hydrochloric acid solutions
Starkov,Patrushev
, p. 312 - 312 (2007)
A new method for the synthesis of [Pt2(NH3) 4P2O7] is proposed. Its transformations in a hydrochloric acid medium are described. Nauka/Interperiodica 2007.
Synthesis and Cytotoxic Study of a Platinum(IV) Anticancer Prodrug with Selectivity toward Luteinizing Hormone-Releasing Hormone (LHRH) Receptor-Positive Cancer Cells
Yao, Houzong,Xu, Zoufeng,Li, Cai,Tse, Man-Kit,Tong, Zixuan,Zhu, Guangyu
, p. 11076 - 11084 (2019)
Platinum drugs including cisplatin are widely used in clinics to treat various types of cancer. However, the lack of cancer-cell selectivity is one of the major problems that lead to side effects in normal tissues. Luteinizing hormone-releasing hormone (LHRH) receptors are overexpressed in many types of cancer cells but rarely presented in normal cells, making LHRH receptor a good candidate for cancer targeting. In this study, we report the synthesis and cytotoxic study of a novel platinum(IV) anticancer prodrug functionalized with LHRH peptide. This LHRH-platinum(IV) conjugate is highly soluble in water and quite stable in a PBS buffer. Cytotoxic study reveals that the prodrug selectively targets LHRH receptor-positive cancer cell lines with the cytotoxicities 5-8 times higher than those in LHRH receptor-negative cell lines. In addition, the introduction of LHRH peptide enhances the cellular accumulation in a manner of receptor-mediated endocytosis. Moreover, the LHRH-platinum(IV) prodrug is proved to kill cancer cells by binding to the genomic DNA, inducing apoptosis, and arresting the cell cycle at the G2/M phase. In summary, we report a novel LHRH-platinum(IV) anticancer prodrug having largely improved selectivity toward LHRH receptor-positive cancer cells, relative to cisplatin.
Microwave-assisted synthesis of the anticancer drug cisplatin, cis-[Pt(NH3)2Cl2]
Petruzzella, Emanuele,Chirosca, Cristian V.,Heidenga, Cameron S.,Hoeschele, James D.
, p. 3384 - 3392 (2015)
A microwave-assisted synthesis of cisplatin, cis-[Pt(NH3)2Cl2], has been developed and optimized on both a 0.2 and 0.05 millimolar scale. The optimized synthetic procedure was modeled after the Lebedinskii-Golovnya method and is suitable for incorporating the radionuclide, 195mPt, into cisplatin for biological studies. Highest yields (47%) and purity are obtained using a K2PtCl4:NH4OAc:KCl molar ratio of 1:4:2 at a temperature of 100 °C. The entire synthesis and purification procedure requires approximately 80 min. At a reaction temperature of 150 °C, the trans isomer is the exclusive product, suggesting that complexes of the general form, trans-[Pt(RNH2)2Cl2], can be synthesized directly from K2PtCl4 using [RNH3]OAc (R = alkyl or aryl moieties) via a microwave process. Two novel separation procedures have been developed which efficiently remove the major impurity (1:1 Magnus-type salt) from the crude reaction product, yielding a product of purity comparable to that obtained by the Dhara method and suitable for biological studies. These procedures are applicable to both the micro- and macro-scale of synthesis. The question of whether this microwave-assisted synthesis of cisplatin will be a preferred method for incorporating 195mPt into cisplatin is yet to be determined. This journal is
A 1,2-d(GpG) cisplatin intrastrand cross-link influences the rotational and translational setting of DNA in nucleosomes
Ober, Matthias,Lippard, Stephen J.
, p. 2851 - 2861 (2008)
The mechanism of action of platinum-based anticancer drugs such as cis-diamminedichloro-platinum(II), or cisplatin, involves three early steps: cell entry, drug activation, and target binding. A major target in the cell, responsible for the anticancer activity, is nuclear DNA, which is packaged in nucleosomes that comprise chromatin. It is important to understand the nature of platinum-DNA interactions at the level of the nucleosome. The cis-{Pt(NH 3)2}2+ 1,2-d(GpG) intrastrand cross-link is the DNA lesion most commonly encountered following cisplatin treatment. We therefore assembled two site-specifically platinated nucleosomes using synthetic DNA containing defined cis-{Pt(NH3)2}2+ 1,2-d(GpG) cross-links and core histones from HeLa-S3 cancer cells. The structures of these complexes were investigated by hydroxyl radical footprinting and exonuclease III mapping. Our experiments demonstrate that the 1,2-d(GpG) cross-link alters the rotational setting of the DNA on the histone octamer core such that the lesion faces inward, with disposition angles of the major groove relative to the core of ξ ≈ -20° and ξ ≈ 40°. We observe increased solvent accessibility of the platinated DNA strand, which may be caused by a structural perturbation in proximity of the 1,2-d(GpG) cisplatin lesion. The effect of the 1,2-d(GpG) cisplatin adduct on the translational setting of the nucleosomal DNA depends strongly on the position of the adduct within the sequence. If the cross-link is located at a site that is in phase with the preferred rotational setting of the unplatinated nucleosomal DNA, the effect on the translational position is negligible. Minor exonuclease III digestion products in this substrate indicate that the cisplatin adduct permits only those translational settings that differ from one another by integral numbers of DNA helical turns. If the lesion is located out of phase with the preferred rotational setting, the translational position of the main conformation was shifted by 5 bp. Additionally, a fraction of platinated nucleosomes with widely distributed translational positions was observed, suggesting increased nucleosome sliding relative to platinated nucleosomes containing the 1,3-intrastrand d(GpTpG) cross-link investigated previously (Ober, M.; Lippard, S. J. J. Am. Chem. Soc. 2007, 129, 6278-6286).
Oxidation of 3,6-dioxa-1,8-octanedithiol by platinum(IV) anticancer prodrug and model complex: Kinetic and mechanistic studies
Huo, Shuying,Shen, Shigang,Liu, Dongzhi,Shi, Tiesheng
, p. 6522 - 6528 (2012)
Thioredoxins are small redox proteins and have the active sites of Cys-Xaa-Yaa-Cys; they are overexpressed by many different cancer cells. Cisplatin and Pt(II) analogues could bind to the active sites and inhibit the activities of the proteins, as demonstrated by other researchers. Platinum(IV) anticancer drugs are often regarded as prodrugs, but their interactions with thioredoxins have not been studied. In this work, 3,6-dioxa-1,8-octanedithiol (dithiol) was chosen as a model compound for the active sites of thioredoxins, and its reactions with cis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4]2- (cisplatin prodrug and a model complex) were studied. The pKa values for the dithiol were characterized to be 8.7 ± 0.2 and 9.6 ± 0.2 at 25.0 °C and an ionic strength of 1.0 M. The reaction kinetics was followed by a stopped-flow spectrophotometer over a wide pH range. An overall second-order rate law was established, -d[Pt(IV)]/dt = k′[Pt(IV)][dithiol], where k′ stands for the observed second-order rate constants. Values of k′ increased several orders of magnitude when the solution pH was increased from 3 to 9. A stoichiometry of Δ[Pt(IV)]/Δ[dithiol] = 1:1 derived for the reduction process and product analysis by mass spectrometry indicated that the dithiol was oxidized to form an intramolecular disulfide, coinciding with the nature of thioredoxin proteins. All of the reaction features are rationalized in terms of a reaction mechanism, involving three parallel rate-determining steps depending on the pH of the reaction medium. Rate constants for the rate-determining steps were evaluated. It can be concluded that Pt(IV) anticancer prodrugs can oxidize the reduced thioredoxins, and the oxidation mechanism is similar to those of the oxidations of biologically important reductants by some reactive oxygen species (ROS) such as hypochlorous acid/hypochlorite and chloramines.
Biological activity of a series of cisplatin-based aliphatic bis(carboxylato) Pt(IV) prodrugs: How long the organic chain should be?
Zanellato, Ilaria,Bonarrigo, Ilaria,Colangelo, Donato,Gabano, Elisabetta,Ravera, Mauro,Alessio, Manuela,Osella, Domenico
, p. 219 - 227 (2014)
The biological properties of a series of cisplatin-based Pt(IV) prodrug candidates, namely trans,cis,cis-[Pt(carboxylato)2Cl 2(NH3)2], where carboxylato = CH 3(CH2)nCOO- [(1), n = 0; (2), n = 2; (3), n = 4; (4), n = 6] having a large interval of lipophilicity are discussed. The stability of the complexes was tested in different pH conditions (i.e. from 1.0 to 9.0) to simulate the hypothetical conditions for an oral route of administration, showing a high stability (> 90%). The transformation into their active Pt(II) metabolites was demonstrated in the presence of ascorbic acid, with a pseudo-first order kinetics, the half-time of which smoothly decreases as the chain length of carboxylic acid increases. Their antiproliferative activity has been evaluated in vitro on a large panel of human cancer cell lines. As expected, the potency increases with the chain length: 3 and 4 resulted by far more active than cisplatin on all cell lines of about one or two orders of magnitude, respectively. Both complexes retained their activity also on cisplatin-resistant cell line, and exhibited a progressive increase of the selectivity compared with non-tumor cells. These results were confirmed with more prolonged treatment (up to 14 days) studied on multicellular tumor spheroids (MCTSs). In this case the Pt(IV) complexes exert a protracted antiproliferative action, even if the drug is removed from the culture medium. Finally, in a time-course experiment of the total platinum evaluation in mice blood (after a single oral administration of the title complexes), 2 gave the best results, representing a good compromise between lipophilicity and water solubility, that increase and decrease respectively on passing from 1 to 4.
Reduction of the anti-cancer drug analogue cis,trans,cis-[PtCl2(OCOCH3)2(NH 3)2] by L-cysteine and L-methionine and its crystal structure
Chen, Lie,Lee, Peng Foo,Ranford, John D.,Vittal, Jagadese J.,Wong, Siew Ying
, p. 1209 - 1212 (1999)
The complex cis,trans,cis-[PtCl2(OCOCH3)2(NH 3)2] 1 has been synthesized as a simplified and more soluble model of the anticancer drug cis,trans,cis-[PtCl2(OCOCH3)2(NH 3)(C6H11NH2)] (JM216). The crystal structure of 1 shows an octahedral co-ordination sphere around the PtIV with strong intramolecular and weak intermolecular hydrogen bonding. The kinetics of reduction of 1 by the divalent sulfur amino acids L-cysteine and L-methionine has been determined over a range of pH values by multinuclear NMR. The reduction is strongly pH dependent, being related to the protonation state of the amino acid and the basicity of the sulfur. Reduction rates are dramatically slower than for previous models of platinum(IV) drug systems.
Preparation of cisplatin using microwave heating and continuous-flow processing as tools
Pedrick, Elizabeth A.,Leadbeater, Nicholas E.
, p. 481 - 483 (2011)
Microwave heating has been used for the small-scale preparation of cisplatin, [cis-PtCl2(NH3)2], in isomerically pure form without concomitant formation of Magnus' salt, [Pt(NH 3)4][PtCl4].
Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues
Chen, Shu,Gunawan, Yuliana F.,Tse, Man-Kit,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
, (2020)
Platinum(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types of ligands will provide us with new insights and more choices to design novel Pt(IV) complexes. In this study, we systematically investigated and compared the properties of Pt(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.
Fighting against Drug-Resistant Tumors using a Dual-Responsive Pt(IV)/Ru(II) Bimetallic Polymer
Butt, Hans-Jürgen,Han, Jianxiong,Liang, Xing-Jie,Sun, Wen,Wang, Yufei,Wu, Si,Zeng, Xiaolong
, (2020)
Drug resistance is a major problem in cancer treatment. Herein, the design of a dual-responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin-resistant tumors in a patient-derived xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA-type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction-responsive Pt(IV) and red-light-responsive Ru(II) moieties. PolyPt/Ru self-assembles into nanoparticles that are efficiently taken up by cisplatin-resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates 1O2, induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated 1O2 have different anticancer mechanisms; their synergistic effects inhibit the growth of drug-resistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli-responsive multi-metallic polymers provides a new strategy to overcome drug resistance.
INORGANIC-ORGANIC HYBRID COMPOUNDS INCLUDING ORGANIC PLATINUM-CONTAINING ANIONS, FOR USE IN MEDICINE
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Paragraph 0080; 0088, (2021/09/26)
The present invention relates to inorganic-organic hybrid compounds for use in medicine or for use as medication, consisting of an inorganic metal cation and an organic platinum-containing cytostatic anion, in particular also a cisplatin derivative.
trans-Platinum(iv) pro-drugs that exhibit unusual resistance to reduction by endogenous reductants and blood serum but are rapidly activated inside cells:1H NMR and XANES spectroscopy study
Chen, Catherine K. J.,Gibson, Dan,Hambley, Trevor W.,Kappen, Peter
supporting information, p. 7722 - 7736 (2020/06/26)
Recent results have confirmed that protection of transplatin from reactions on the path to cancer cells substantially increases their activity, suggesting that such complexes have greater potential than previously thought. In this study we have investigated the use of the platinum(iv) oxidation state and the tetracarboxylate coordination sphere to determine whether these features could impart the same stability totrans-diammineplatinum complexes that they do tocis-diam(m)ineplatinum complexes. Theciscomplexes exhibit resistance to reduction byl-ascorbate and human blood serum, but are readily reduced inside cancer cells. Studies of reduction monitored by1H NMR revealed that oxidation oftrans-diammineplatinum(ii) complexes does not always result in significant stabilisation, but the complexestrans, trans, trans-[Pt(OAc)4(NH3)2] (OAc = acetate) andtrans, trans, trans-[Pt(OPr)2(OAc)2(NH3)2] (OPr = propionate) exhibit second order half-lives of 33 h and 5.9 days respectively in the presence of a ten-fold excess ofl-ascorbate. XANES spectroscopy studies of reduction in blood models showed thattrans, trans, trans-[Pt(OAc)4(NH3)2] is stable in blood serum for at least 24 hours, but is reduced rapidly in whole blood and was observed to have a half-life of approximately 4 hours in DLD-1 colon cancer cells. Consequently, the tetracarboxylatoplatinum(iv) moiety has the properties required to enable the delivery oftrans-diammine platinum complexes to cancer cells.