- Copper-free click-chemistry platform to functionalize cisplatin prodrugs
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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.
- Pathak, Rakesh K.,McNitt, Christopher D.,Popik, Vladimir V.,Dhar, Shanta
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- Glassy carbon electrodes deliver unpredictable reduction potentials for platinum(IV) antitumor prodrugs
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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.
- McCormick, Meghan C.,Schultz, Franklin A.,Baik, Mu-Hyun
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- Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs
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A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin-sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion. While Pt(IV) complexes having lipophilicity comparable to that of cisplatin (negative values of log Po/w) exhibit a cellular accumulation similar to that of cisplatin, the most lipophilic complexes of the series show much higher cellular accumulation (stemming from enhanced passive diffusion), accompanied by greater DNA platination and cell growth inhibition. Even if the Pt(IV) complexes are removed from the culture medium in the recovery process, the level of DNA platination remains very high and persistent in time, indicating efficient storing of the complexes and poor detoxification efficiency.
- Ravera, Mauro,Gabano, Elisabetta,Zanellato, Ilaria,Bonarrigo, Ilaria,Alessio, Manuela,Arnesano, Fabio,Galliani, Angela,Natile, Giovanni,Osella, Domenico
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- Kinetic characterization of the interactions of trans-dichloro-platinum(IV) anticancer prodrugs and a model compound with thiosulfate
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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.
- Dong, Jingran,Huo, Shuying,Song, Changying,Shen, Shigang,Ren, Yanli,Shi, Tiesheng
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- Synthesis of pyrophosphatotetraamminediplatinum(II) complex and its transformations in hydrochloric acid solutions
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A new method for the synthesis of [Pt2(NH3) 4P2O7] is proposed. Its transformations in a hydrochloric acid medium are described. Nauka/Interperiodica 2007.
- Starkov,Patrushev
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- Bioorthogonal Catalytic Activation of Platinum and Ruthenium Anticancer Complexes by FAD and Flavoproteins
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Recent advances in bioorthogonal catalysis promise to deliver new chemical tools for performing chemoselective transformations in complex biological environments. Herein, we report how FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), and fo
- Alonso-de Castro, Silvia,Cortajarena, Aitziber L.,López-Gallego, Fernando,Salassa, Luca
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- Synthesis and Cytotoxic Study of a Platinum(IV) Anticancer Prodrug with Selectivity toward Luteinizing Hormone-Releasing Hormone (LHRH) Receptor-Positive Cancer Cells
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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.
- Yao, Houzong,Xu, Zoufeng,Li, Cai,Tse, Man-Kit,Tong, Zixuan,Zhu, Guangyu
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- Carboplatin decomposition in aqueous solution with chloride ions monitored by X-ray absorption spectroscopy
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Carboplatin aqueous solutions, with chloride ions added at different concentrations, were studied by X-ray absorption spectroscopy (XAS). The comparison of solid and solution spectra shows that carboplatin and cisplatin spectra are strongly different, and that the carboplatin ligands induce a specific structure of the spectrum, conserved in solution. Hence, it is possible to study by XAS the evolution of carboplatin in solution. This study shows that carboplatin is the major compound present in solution, even after 15 days, in neutral solutions with chloride concentration less than 9%, exposed to light or not. On the contrary, with high chloride concentrations (18%) or in acidic solutions (0.1 M HCl), the carboplatin is chlorolysed, the evolution of the solution composition can be followed by XAS and cisplatin formation is evidenced.
- Curis,Provost,Nicolis,Bouvet,Benazeth,Crauste-Manciet,Brion,Brossard
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- Microwave-assisted synthesis of the anticancer drug cisplatin, cis-[Pt(NH3)2Cl2]
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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
- Petruzzella, Emanuele,Chirosca, Cristian V.,Heidenga, Cameron S.,Hoeschele, James D.
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- Aluminum Doped MCM-41 Nanoparticles as Platforms for the Dual Encapsulation of a CO-Releasing Molecule and Cisplatin
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Mesoporous silica Al-MCM-41 nanoparticles have been used, for the first time, as vehicles for the single and dual encapsulation of the cationic CO-releasing molecule (CORM) [Mn(1,4,7-triazacyclononane)(CO)3]+ (ALF472+) and the well-known antineoplastic drug, cis-[PtCl2(NH3)2] (cisplatin). Thus, two new hybrid materials, namely, ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41, have been isolated and fully characterized. The results reveal that the presence of CORM molecules enhances cisplatin loading 3-fold, yielding a cargo of 0.45 mmol g-1 of ALF472+ and 0.12 mmol g-1 of the platinum complex for ALF472-cisplatin@Al-MCM-41. It is worth noting that ALF472@Al-MCM-41 shows a good dispersion in phosphate buffered saline solution, while the dual hybrid material slightly aggregates in this simulated physiological medium (hydrodynamic size: 112 ± 23 and 336 ± 50 nm, respectively). In addition, both hybrid materials (ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41) behave as photoactive CO-releasing materials, delivering 0.25 and 0.11 equiv of CO, respectively, after 24 h and exhibiting a more controlled CO delivery than that of the free CORM. Finally, metal leaching studies have confirmed the good retention capacity of Al-MCM-41 toward the potentially toxic manganese fragments (86% of retention after 72 h) as well as the low release of cisplatin (ca. 7% after 72 h).
- Carmona, Francisco J.,Jiménez-Amezcua, Ignacio,Rojas, Sara,Rom?o, Carlos C.,Navarro, Jorge A. R.,Maldonado, Carmen R.,Barea, Elisa
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- A 1,2-d(GpG) cisplatin intrastrand cross-link influences the rotational and translational setting of DNA in nucleosomes
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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).
- Ober, Matthias,Lippard, Stephen J.
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- In vitro anticancer active cis-Pt(II)-diiodido complexes containing 4-azaindoles
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4-Azaindole (1H-pyrrolo[3,2-b]pyridine; 4aza) and its N1-alkylated derivative N1-isopropyl-4-azaindole (1-(propan-2-yl)-1H-pyrrolo[3,2-b]pyridine; ip4aza) have been used for the preparation of the cis-diiodido-platinum(II) complexes cis-[Pt(4aza)2I2] (1), cis-[PtI2(ip4aza)2] (2), cis-[Pt(4aza)I2(NH3)] (3) and cis-[PtI2(ip4aza)(NH3)] (4). The prepared complexes were thoroughly characterized (e.g., multinuclear NMR spectroscopy and ESI mass spectrometry) and their in vitro cytotoxicity was assessed at human ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R) and colon carcinoma (HT-29) cell lines, where they showed, in some cases, significantly higher activity than the used reference-drug cisplatin. The results of in vitro cytotoxicity testing at the A2780 and A2780R cells indicated that alkylation of the 4-azaindole moiety at the position of the N1 atom had a positive biological effect, because the ip4aza-containing complexes 2 and 4 showed significantly (p 0.005) higher cytotoxicity than 4aza-containing analogues 1 and 3. The resistance factors (A2780R/A2780 model) equalled 0.8–1.4, indicating the ability of complexes 1–4 to overcome the acquired resistance of the A2780 cells against cisplatin. Complexes 1 and 2 revealed low toxicity against primary culture of human hepatocytes. The flow cytometry studies of the A2780 cell cycle modification showed that complexes 1–4 induce different cell cycle perturbations as compared with cisplatin, thus suggesting a different mechanism of their antitumor action.
- ?tarha, Pavel,Trávní?ek, Zdeněk,Van?o, Ján,Dvo?ák, Zdeněk
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- Oxidation of 3,6-dioxa-1,8-octanedithiol by platinum(IV) anticancer prodrug and model complex: Kinetic and mechanistic studies
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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.
- Huo, Shuying,Shen, Shigang,Liu, Dongzhi,Shi, Tiesheng
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- Riboflavin as a bioorthogonal photocatalyst for the activation of a PtIV prodrug
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Encouraging developments demonstrate that few transition metal and organometallic catalysts can operate in a bioorthogonal fashion and promote non-natural chemistry in living systems by minimizing undesired side reactions with cellular components. These catalytic processes have potential for applications in medicinal chemistry and chemical biology. However, the stringent conditions of the cell environment severely limit the number of accessible metal catalysts and exogenous reactions. Herein, we report an unorthodox approach and a new type of bioorthogonal catalytic reaction, in which a metal complex is an unconventional substrate and an exogenous biological molecule acts as a catalyst. In this reaction, riboflavin photocatalytically converts a PtIV prodrug into cisplatin within the biological environment. Due to the catalytic activity of riboflavin, cisplatin-like apoptosis is induced in cancer cells under extremely low doses of light, potentially preventing systemic off-target reactions. Photocatalytic and bioorthogonal turnover of PtIV into PtII species is an attractive strategy to amplify the antineoplastic action of metal-based chemotherapeutics with spatio-temporal control.
- Alonso-De Castro, Silvia,Ruggiero, Emmanuel,Ruiz-De-Angulo, Ane,Rezabal, Elixabete,Mareque-Rivas, Juan C.,Lopez, Xabier,López-Gallego, Fernando,Salassa, Luca
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- Biological activity of a series of cisplatin-based aliphatic bis(carboxylato) Pt(IV) prodrugs: How long the organic chain should be?
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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.
- Zanellato, Ilaria,Bonarrigo, Ilaria,Colangelo, Donato,Gabano, Elisabetta,Ravera, Mauro,Alessio, Manuela,Osella, Domenico
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- Photoinduced reduction of PtIV within an anti-proliferative PtIV-texaphyrin conjugate
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In an effort to increase the stability and control the platinum reactivity of platinum-texaphyrin conjugates, two PtIV conjugates were designed, synthesized, and studied for their ability to form DNA adducts. They were also tested for their anti-proliferative effects using wild-type and platinum-resistant human ovarian cancer cell lines (A2780 and 2780CP, respectively). In comparison to an analogous first-generation PtII chimera, one of the new conjugates provided increased stability in aqueous environments. Using a combination of 1H NMR spectroscopy and FAAS (flameless atomic-absorption spectrometry), it was found that the Pt IV center within this conjugate undergoes photoinduced reduction to PtII upon exposure to glass-filtered daylight, resulting in an entity that binds DNA in a controlled manner. Under conditions in which the Pt IV complex is reduced to the corresponding PtII species, these new conjugates demonstrated potent anti-proliferative activity in both test ovarian cancer cell lines. Platinum(IV) prodrug: Two new platinum(IV)-texaphyrin conjugates were designed and synthesized in order to target preferentially cancer cells and to deliver platinum(II). Protected from light, these two compounds are stable in aqueous environments. However, upon reduction or upon exposure to visible light, an active PtII species is released and binds to DNA. Potent anti-proliferative activity in test ovarian cancer cell lines was also seen for the PtIV-texaphyrin conjugates of this study.
- Thiabaud, Gregory,Arambula, Jonathan F.,Siddik, Zahid H.,Sessler, Jonathan L.
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- 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
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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.
- Chen, Lie,Lee, Peng Foo,Ranford, John D.,Vittal, Jagadese J.,Wong, Siew Ying
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- Immuno-chemotherapeutic platinum(IV) prodrugs of cisplatin as multimodal anticancer agents
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There is growing consensus that the clinical therapeutic efficacy of some chemotherapeutic agents depends on their off-target immune-modulating effects. Pt anticancer drugs have previously been identified to be potent immunomodulators of both the innate and the adaptive immune system. Nevertheless, there has been little development in the rational design of Pt-based chemotherapeutic agents to exploit their immune-activating capabilities. The FPR1/2 formyl peptide receptors are highly expressed in immune cells, as well as in many metastatic cancers. Herein, we report a rationally designed multimodal PtIV prodrug containing a FPR1/2-targeting peptide that combines chemotherapy with immunotherapy to achieve therapeutic synergy and demonstrate the feasibility of this approach. Two-pronged attack: A cisplatin prodrug was developed with the ability to induce cancer cell death through two distinct pathways, targeted direct cytotoxicity and activation of innate immune cells for cell-mediated cytotoxicity, to realize the concept of a multimodal immuno-chemotherapeutic approach (see figure; m: D-Met).
- Wong, Daniel Yuan Qiang,Yeo, Charmian Hui Fang,Ang, Wee Han
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- Preparation of cisplatin using microwave heating and continuous-flow processing as tools
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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].
- Pedrick, Elizabeth A.,Leadbeater, Nicholas E.
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- Study of the Structure and Reactions of Bis(μ-Oxalato)tetramminediplatinum(II) in Aqueous Chloride Solutions
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A comparison study of the bis(μ-oxalato)tetramminediplatinum(II) dimer [Pt2(NH3)4(μ-C2O 4)2] and the oxalatodiammineplatinum(II) chelate [Pt(NH3)2C2O4] is performed. The kinetics and mechanism of substitution of C2O42- for Cl- in aqueous chloride solutions are studied by photoelectronic spectroscopy, gravimetry, and chemical phase analysis within the 1.0-6.7 pH range at 75°C. The rate constants of substitution and the equilibrium constants for a two-step protonation for the dimeric and chelate complexes are calculated. Their solubility in 1 M KCl at 75°C is determined. The unit cell parameters for [Pt2(NH3)4(μ-C2O 4)2] are determined: a = 3.858 A, b = 10.704 A, c = 6.795 A, β = 94.35°. The IR spectra of [Pt(NH3)2C2O4], [Pt2(NH3)4(μ-C2O 4)2], and their deuterated analogs are studied.
- Kazbanov,Starkov,Kozhukhovskaya,Kazbanova,Trofimov,Pavlenko
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- Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues
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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.
- Chen, Shu,Gunawan, Yuliana F.,Tse, Man-Kit,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
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- Cancer-Specific, Intracellular, Reductive Activation of Anticancer PtIV Prodrugs
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Because cellular uptake of anticancer PtII and PtIV drugs occurs by different mechanisms, the latter ones can exhibit substantial activity towards cells, which have either intrinsic or acquired resistance towards PtII drugs. However, this positive effect is diminished due to reductive activation of PtIV drugs in extracellular space that can be one of the reasons why they have not yet been approved for clinical use despite over 60 clinical trials conducted worldwide. Herein, we suggest a solution to this problem by achieving highly specific intracellular versus extracellular prodrug reduction. In particular, we prepared a hybrid PtIV prodrug containing two pro-reductants. This hybrid was uptaken by cells, the pro-reductants were activated in the cancer-specific microenvironment (high H2O2), and reduced PtIV by two one-electron transfers. The drug formed in this way induced cell death both in cisplatin-sensitive and resistant cell lines, but remained nontoxic to normal cells.
- Reshetnikov, Viktor,Daum, Steffen,Mokhir, Andriy
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- Fighting against Drug-Resistant Tumors using a Dual-Responsive Pt(IV)/Ru(II) Bimetallic Polymer
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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.
- Butt, Hans-Jürgen,Han, Jianxiong,Liang, Xing-Jie,Sun, Wen,Wang, Yufei,Wu, Si,Zeng, Xiaolong
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- The influence of different carbonate ligands on the hydrolytic stability and reduction of platinum(
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Pt(iv) complexes bearing axial carbonate linkages have drawn much attention recently. A synthetic method behind this allows the hydroxyl group of bioactive ligands to be attached to the available hydroxyl group of Pt(iv) complexes, and the rapid release of free drugs is achieved after the reduction of carbonate-linked Pt(iv) complexes. Further understanding on the properties of Pt(iv) carbonates such as hydrolytic stability and reduction profiles, however, is hindered by limited research. Herein, six mono-carbonated Pt(iv) complexes in which the carbonate axial ligands possess various electron-withdrawing powers were synthesized, and the corresponding mono-carboxylated analogues were also prepared as references to highlight the different properties. The influence of the coordination environment towards the hydrolysis and reduction rate of Pt(iv) carbonates and carboxylates was explored. The mono-carbonated Pt(iv) complexes are both less stable and reduced faster than the corresponding mono-carboxylated ones. Moreover, the hydrolysis and reduction profiles are dependent not only on the electron-withdrawing ability of the carbonates but also on the nature of the opposite axial ligands. Besides, the exploration of the hydrolytic pathway for Pt(iv) carbonates suggests that the process proceeds by an attack of OH? on the carbonyl carbon, followed by elimination, which is different from that of Pt(iv) carboxylates. This study provides some information on the influence of axial carbonate ligands with different electron-withdrawing abilities on the properties of the Pt(iv) center, which may inspire new thoughts on the design of “multi-action” Pt(iv) prodrugs.
- Chen, Shu,Deng, Zhiqin,Ng, Ka-Yan,Tse, Man-Kit,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
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supporting information
p. 885 - 897
(2022/02/01)
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- Gold(Iii) to ruthenium(iii) metal exchange in dithiocarbamato complexes tunes their biological mode of action for cytotoxicity in cancer cells
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Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts have been spent in the last decades on achieving an early stage diagnosis of cancer, and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes, with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes that share the piperidine dithiocarbamato (pipe-DTC) as the ligand, in a different molar ratio. The compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and β-[Ru2(pipeDTC)5] have been synthesized and fully characterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely, AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and β-[Ru2(pipeDTC)5] display IC50 in the μM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and β-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced the ATF4 protein level, but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand depends on the electronic and structural properties of the metal, which are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs.
- Brustolin, Leonardo,Dalla Pozza, Maria,Fregona, Dolores,Gaiddon, Christian,Nardon, Chiara,Orvain, Christophe,Pettenuzzo, Nicolò
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supporting information
(2021/07/19)
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- INORGANIC-ORGANIC HYBRID COMPOUNDS INCLUDING ORGANIC PLATINUM-CONTAINING ANIONS, FOR USE IN MEDICINE
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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.
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Paragraph 0080; 0088
(2021/09/26)
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- A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance
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Platinum(Pt)(II) drugs and new Pt(IV) agents behave the dysregulation of apoptosis as the result of DNA damage repair and thus, are less effective in the treatment of resistant tumors. Herein, mononitro-naphthalimide Pt(IV) complex 10b with minimized side-effects was reported targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance. 10b displayed remarkably evaluated antitumor (70.10percent) activities in vivo compared to that of cisplatin (52.88percent). The highest fold increase (FI) (5.08) for A549cisR cells and the lowest (0.72) for A549 indicated 10b preferentially accumulated in resistant cell lines. The possible molecular mechanism indicates that 10b targets resistant cells in a totally different way from the existing Pt drugs. The cell accumulation and the Pt levels in genomic DNA from 10b is almost 5 folds higher than that of cisplatin and oxaliplatin, indicating the naphthalimide moiety in 10b exhibits preferentially DNA damage. Using 5′-dGMP as a DNA model, the DNA-binding properties of 10b (1 mM) with 5′-dGMP (3 mM) in the presence of ascorbic acid (5 mM) deduced that 10b was generated by the combination of cisplatin with 5′-dGMP after reduction by ascorbic acid. Moreover, 10b promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity. The up-regulated γH2A.X and down-regulated RAD51 indicates that 10b not only induced severe DNA damage but also inhibited the DNA damage repair, thus resulting in its higher cytotoxicity in comparison to that of cisplatin. Their preferential accumulation in cancer cells (SMMC-7721) compared to the matched normal cells (HL-7702 cells) demonstrated that they were potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 10b for 4T1 cells in vivo indicated that naphthalimide-Pt(IV) conjugates behaved a vital function in the treatment of breast cancer. For the first time, our study implies a significant strategy for Pt drugs to treat resistance cancer targeting DNA damage repair via dual DNA damage mechanism in a totally new field.
- Li, Linrong,Li, Yingguang,Liu, Hanfang,Ma, Jing,Niu, Jie,Xie, Songqiang,Yue, Kexin
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- Solid-Phase Reaction of Tetraammineplatinum(II) Chloride with Ammonium Heptamolybdate
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Abstract: The solid-phase reaction of [Pt(NH3)4]Cl2 and (NH4)6Mo7O24 under argon in the temperature range from 50 to 500°C was studied by thermal analysis and mass spectrometry.
- Buslaeva, T. M.,Fesik, E. V.,Melnikova, T. I.,Tarasova, L. S.
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p. 1020 - 1024
(2020/07/27)
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- 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
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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.
- Chen, Catherine K. J.,Gibson, Dan,Hambley, Trevor W.,Kappen, Peter
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supporting information
p. 7722 - 7736
(2020/06/26)
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- Anti-tumor platinum (IV) complexes bearing the anti-inflammatory drug naproxen in the axial position
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The role of inflammation in cancer generation is gaining importance in the field of cancer research. The chemo-anti-inflammatory strategy that involves using non-steroidal anti-inflammatory drug compounds as effective anti-tumor agents is being acceded globally. In the present study, seven new Pt (IV) complexes based on cisplatin, carboplatin and oxaliplatin scaffold bearing the anti-inflammatory drug naproxen in the axial position were synthesized and characterized by elemental analysis, ESI-MS, Fourier transform-infrared, 1H- and 195Pt-NMR spectroscopy. The reduction behavior in the presence of ascorbic acid was studied using high-performance liquid chromatography. The cytotoxicity against two human breast cell lines and the anti-inflammatory properties were evaluated. All the complexes are able to promote a comparable activity, with average three- and 13-fold more cytotoxic than cisplatin against MCF7 and MDA-MB-231 cell lines, respectively. The complexes show remarkable anti-inflammatory effects, which indicated their potential in treating cancer associated with inflammation and reducing side-effects of chemotherapy.
- Tolan, Dina A.,Abdel-Monem, Yasser K.,El-Nagar, Mohamed A.
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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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- Development of an Efficient Dual-Action GST-Inhibiting Anticancer Platinum(IV) Prodrug
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The cytotoxicity of cisplatin (cDDP) is enhanced when co-administered with ethacrynic acid (EA), a glutathione S-transferase (GST) inhibitor. A PtIV–EA conjugate containing a cDDP core and two axial ethacrynate ligands (compound 1) was shown to be an excellent inhibitor of GST, but did not readily release a PtII species to exert a synergistic cytotoxic effect. In this study, a redesigned PtIV construct composed of a cDDP core with one axial ethacrynate ligand and one axial hydroxido ligand (compound 2) was prepared and shown to overcome the limitations of compound 1. The EA ligand in 2 is readily released in vitro together with a cytotoxic PtII species derived from cisplatin, working together to inhibit cell proliferation in cDDP-resistant human ovarian cancer cells. The in vitro activity translates well in vivo with 2, showing effective (～80 %) inhibition of tumor growth in a human ovarian carcinoma A2780 tumor model, while showing considerably lower toxicity than cisplatin, thus validating the new design strategy.
- Lee, Keefe Guang Zhi,Babak, Maria V.,Weiss, Andrea,Dyson, Paul J.,Nowak-Sliwinska, Patrycja,Montagner, Diego,Ang, Wee Han
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p. 1210 - 1217
(2018/06/04)
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- METAL COMPLEX AND ANTICANCER AGENT CONTAINING THE SAME AS ACTIVE INGREDIENT
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PROBLEM TO BE SOLVED: To provide a novel complex that has excellent anticancer activity and can be orally administered, and an anticancer agent containing the same as an active ingredient. SOLUTION: An anticancer agent contains a metal complex represented by the following formula [2] or a salt thereof as an active ingredient. SELECTED DRAWING: Figure 17 COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0059
(2018/09/26)
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- Coordination-drIVen self-assembly of a Pt(IV) prodrug-conjugated supramolecular hexagon
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This article presents a new strategy to engage coordination-driven self-assembly for platinum drug delivery. The self-assembled supramolecular hexagon is conjugated with three equivalents of Pt(iv) prodrugs and displays a superior therapeutic index compared to cisplatin against a panel of human cancer cell lines.
- Yue, Zhizhou,Wang, Han,Li, Yiming,Qin, Yi,Xu, Lin,Bowers, David J.,Gangoda, Mahinda,Li, Xiaopeng,Yang, Hai-Bo,Zheng, Yao-Rong
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supporting information
p. 731 - 734
(2018/02/06)
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- The effect of geometric isomerism on the anticancer activity of the monofunctional platinum complex: Trans -[Pt(NH3)2(phenanthridine)Cl]NO3
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A trans-DDP based monofunctional phenanthridine Pt(ii) complex was synthesized and characterized. Its anticancer activity was studied in vitro on a panel of human cancer cell lines and mouse intestinal cancer organoids. This complex displays significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin.
- Zhou, Wen,Almeqdadi, Mohammad,Xifaras, Michael E.,Riddell, Imogen A.,Yilmaz, ?mer H.,Lippard, Stephen J.
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supporting information
p. 2788 - 2791
(2018/03/21)
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- Reduction of Cisplatin and Carboplatin Pt(IV) Prodrugs by Homocysteine: Kinetic and Mechanistic Investigations
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Pt(IV) anticancer active complexes are commonly regarded as prodrugs, and the reduction of the prodrugs to their Pt(II) analogs is the activation process. The reduction of a cisplatin prodrug cis-[Pt(NH3)2Cl4] and a carboplatin prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] by dl-homocysteine (Hcy) has been investigated kinetically in a wide pH range in this work. The reduction process follows overall second-order kinetics: ?d[Pt(IV)]/dt = k′[Hcy]tot[Pt(IV)], where [Hcy]tot stands for the total concentration of Hcy and k′ pertains to the observed second-order rate constants. The k′ versus pH profiles have been established for both prodrugs. Spectrohotometric titrations reveal a stoichiometry of Δ[Pt(IV)]:Δ[Hcy]tot = 1:2; homocystine is identified as the major oxidation product of Hcy by high-resolution mass spectrometry. A reaction mechanism has been proposed, which involves all the four protolysis species of Hcy attacking the Pt(IV) prodrugs in parallel. Moreover, these parallel attacks are the rate-determining steps, resulting in a Cl+ transfer from the Pt(IV) prodrugs to the attacking sulfur atom. Rate constants of the rate-determining steps have been derived, indicating that the two prodrugs are reduced with a very similar rate in spite of the difference between the coordination ligands in their equatorial positions. The reactivity analysis in the case of cis,trans-[Pt(cbdca)(NH3)2Cl2] unravels that one species of Hcy (form III) is almost exclusively responsible for the reductions at the physiological pH (7.4), although it is existing only 5.2% of the total Hcy. On the other hand, the dominant existing form II of Hcy virtually does not make a contribution to the overall reactivity at pH 7.4.
- Tian, Hongwu,Dong, Jingran,Chi, Xueru,Xu, Liyao,Shi, Hongmei,Shi, Tiesheng
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supporting information
p. 681 - 689
(2017/08/01)
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- Glycosylated platinum(IV) prodrugs demonstrated significant therapeutic efficacy in cancer cells and minimized side-effects
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Conjugates (A1-A5) of the Pt(iv) derivative (A6) with amino groups from peracetyl glucose, rhamnose and mannose with a propyl amino or ethyl amino linker at the reducing end were synthesized and exhibited significant therapeutic efficacy in tumour cells, especially for prostate cancer (PCa). The antitumor activities are greatly affected by glycosyl groups. Cytotoxic experiments in vitro indicated that the antitumor activities were increased by 5-fold when its Pt(iv) derivative was conjugated to S18 (IC50 = 4.82 ± 0.45 μM) and by 12-fold when conjugated to S21 (IC50 = 1.9 ± 0.67 μM). The mannose substituted Pt(iv) complexes A4 and A5 were also over an order of magnitude more potent towards HeLa, A549, MCF-7 and PC3 than cisplatin and oxaliplatin. Importantly, the glycosylated Pt(iv) derivatives A4 and A5 displayed potential safety for clinical therapeutic exposure with IC50 of 84 μM and 169 μM compared with cisplatin (IC50 = 8 μM) to 3T3. Cellular uptake and DNA platination are higher than cisplatin and oxaliplatin. ESI-MS analysis of A5 binding to 5′-dGMP revealed that bifunctional DNA lesions were formed. The antitumor activities in vivo showed that the MTD and LD50 for A4 and A5 are nearly 4-fold higher than that of oxaliplatin indicating the potential safety for the glycosylated Pt(iv) complexes.
- Ma, Jing,Wang, Qingpeng,Yang, Xiande,Hao, Wenpei,Huang, Zhonglv,Zhang, Jiabao,Wang, Xin,Wang, Peng George
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p. 11830 - 11838
(2016/07/29)
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- Chloride triggered reversible switching from a metallosupramolecular [Pd2L4]4+ cage to a [Pd2L2Cl4] metallo-macrocycle with release of endo- and exo-hedrally bound guests
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A metallosupramolecular [Pd2L4]4+ cage can be cleanly converted into a [Pd2L2Cl4] metallo-macrocycle upon addition of chloride ions. The process is reversible, treatment of the [Pd2L2Cl4] macrocycle with silver(i) ions regenerates the [Pd2L4]4+ cage. Additionally, it is shown that guest molecules could be released on chloride triggered cage dis-assembly and taken up anew on re-assembly. This journal is
- Preston, Dan,Fox-Charles, Alyssa,Lo, Warrick K. C.,Crowley, James D.
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supporting information
p. 9042 - 9045
(2015/05/27)
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- Encapsulation of Pt(IV) prodrugs within a Pt(II) cage for drug delivery
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This report presents a novel strategy that facilitates delivery of multiple, specific payloads of Pt(IV) prodrugs using a well-defined supramolecular system. This delivery system comprises a hexanuclear Pt(II) cage that can host four Pt(IV) prodrug guest molecules. Relying on host-guest interactions between adamantyl units tethered to the Pt(IV) molecules and the cage, four prodrugs could be encapsulated within one cage. This host-guest complex, exhibiting a diameter of about 3 nm, has been characterized by detailed NMR spectroscopic measurements. Owing to the high positive charge, this nanostructure exhibits high cellular uptake. Upon entering cells and reacting with biological reductants such as ascorbic acid, the host-guest complex releases cisplatin, which leads to cell cycle arrest and apoptosis. The fully assembled complex displays cytotoxicity comparable to that of cisplatin against a panel of human cancer cell lines, whereas the cage or the Pt(IV) guest alone exhibit lower cytotoxicity. These findings indicate the potential of utilising well-defined supramolecular constructs for the delivery of prodrug molecules.
- Zheng, Yao-Rong,Suntharalingam, Kogularamanan,Johnstone, Timothy C.,Lippard, Stephen J.
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p. 1189 - 1193
(2015/02/19)
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- PRODRUG FOR RELEASE OF CISPLATIN AND CYCLOOXYGENASE INHIBITOR
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Pt(IV) prodrugs include one or more conjugated cyclooxygenase inhibitor. Reduction of Pt(IV) to Pt(II) can result cisplatin and a cyclooxygenase inhibitor. For proof of concept, a Pt(IV) prodrug that can produce cisplatin and aspirin, Platin-A, was synthesized. Platin-A exhibited excellent anticancer and anti-inflammatory properties, which were better than the combination of free formulation of cisplatin and aspirin.
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Paragraph 00104
(2015/06/25)
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- Characterization of the mechanism of reduction of trans-diamminetetrachloroplatinum(IV) by l-cysteine and dl-homocysteine
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The interactions between Pt(IV) anticancer prodrugs incorporating two ammines/amines in trans positions in their equatorial planes and some important thiols have not been exploited to date. In this work, the reduction of one such Pt(IV) prodrug, namely trans-[Pt(NH3)2Cl4], by two thiol-containing amino acids l-cysteine (Cys) and dl-homocysteine (Hcy) which are prevalent in human plasma has been characterized by stopped-flow spectroscopic and ESI high-resolution mass spectral methods. The reduction process obeys overall second-order kinetics. The dependencies of the observed second-order rate constants k′ on pH have been established between pH 4.03 and 11.24. Mass spectral analysis indicates that cystine and homocystine are the dominant products for the Cys and Hcy oxidations, respectively. The suggested reaction mechanism involves all possible protolytic species of Cys/Hcy, which attack one of the two apically coordinated chlorides in parallel (all as rate-determining steps), leading to a Cl+ transfer to the attacking sulfur atom. The rate expression has been derived, and the rate constants for the rate-determining steps have been calculated. Features of the reduction process are discussed based on the obtained rate constants. The overall kinetic and mechanistic picture enables an in-depth understanding of the reduction process of this type of Pt(IV) anticancer prodrug.
- Lu, Taotao,Dong, Jingran,Nan, Chunxia,Huo, Shuying,Shen, Shigang,Sun, Sufang,Shi, Tiesheng
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p. 869 - 875
(2015/10/20)
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- Pt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery
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Albumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asymmetrically functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliphatic tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O 2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analogue bearing a fluorophore conjugated to the succinate ligand confirmed that these compounds are reduced by biological reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphology following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extraction with octanol completely removes the prodrug from an aqueous solution of HSA. Construct 7 is robust and can be isolated following fast protein liquid chromatography. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of reduction of the prodrug by ascorbate. The lead compound from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.
- Zheng, Yao-Rong,Suntharalingam, Kogularamanan,Johnstone, Timothy C.,Yoo, Hyunsuk,Lin, Wei,Brooks, Jamar G.,Lippard, Stephen J.
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supporting information
p. 8790 - 8798
(2014/07/07)
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- Molecular interaction fields vs. quantum-mechanical-based descriptors in the modelling of lipophilicity of platinum(iv) complexes
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We report QSAR calculations using VolSurf descriptors to model the lipophilicity of 53 Pt(iv) complexes with a diverse range of axial and equatorial ligands. Lipophilicity is measured using an efficient HPLC method. Previous models based on a subset of these data are shown to be inadequate, due to incompatibility of whole molecule descriptors between carboxylato and hydroxido ligands. Instead, the interaction surfaces of complexes with various probes are used as independent descriptors. Partial least squares modelling using three latent variables results in an accurate (R2 = 0.92) and robust model (Q2 = 0.87) of lipophilicity, that moreover highlights the importance of size and hydrophobicity terms and the modest relevance of hydrogen bonding.
- Ermondi, Giuseppe,Caron, Giulia,Ravera, Mauro,Gabano, Elisabetta,Bianco, Sabrina,Platts, James A.,Osella, Domenico
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supporting information
p. 3482 - 3489
(2013/03/28)
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- A Keggin-type polyoxotungstate-coordinated diplatinum(II) complex: Synthesis, characterization, and stability of the cis-platinum(II) moieties in dimethylsulfoxide and water
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The synthesis of a Keggin-type polyoxotungstate-coordinated diplatinum(II) complex, [(CH3)4N]3[α-PW 11O39{cis-Pt(NH3)2}2], obtained by reaction of Keggin-type mono-lacunary polyoxotungstate, [α-PW11O39]7-, with cis- diamminedichloroplatinum(II) in an aqueous solution is described. The complex was characterized by elemental analysis, thermogravimetric/differential thermal analysis (TG/DTA), Fourier transform infrared (FTIR), ultraviolet-visible (UV-vis), and solution 1H, 31P, and 183W nuclear magnetic resonance (NMR) spectroscopy. The two cis-platinum(II) moieties, [cis-Pt(NH3)2]2+, were coordinated each to two oxygen atoms in a mono-vacant site of [α-PW11O 39]7- with Cs symmetry, and the cis-conformation was highly stable in dimethylsulfoxide and water.
- Kato, Masao,Kato, Chika Nozaki
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p. 982 - 985
(2011/08/05)
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- Conversion of Magnus salt into diamminedichloroplatinum(II) isomers in aqueous solution
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The conditions inducing conversion of Magnus salt into diamminedichloroplatinum(II) isomers were studied. Syntheses of cis-diamminedichloroplatinum(II) and trans-diamminedichloroplatinum(II), which are used to prepare potassium or ammonium amminetrichloroplatinate(II), are described. The identity and structure of diamminedichloroplatinum(II) isomers were verified by elemental analysis, X-ray powder diffraction, and IR and UV spectroscopy. A workflow for preparing potassium or ammonium amminetrichloroplatinate(II) from diamminedichloroplatinum(II) isomers was developed. This workflow appreciably increases the product yield due to the return of unused Magnus salt to the main synthesis flow.
- Starkov,Kozhukhovskaya
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p. 1426 - 1429
(2009/05/06)
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- Synthesis of the isomers of dichlorodiammineplatinum(II) from the magnus salt
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The synthesis of the isomers of dichlorodiammineplatinum (II) from the Magnus salt is described. The Magnus salt is added to an aqueous solution of ammonium acetate. The reaction mixture is heated for an hour and then cooled. hydrochloric acid is added an
- Starkov,Kazbanov,Kozhukhovskaya,Olado
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p. 692 - 692
(2008/10/09)
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- Coordination complexes, and methods for preparing by combinatorial methods, assaying and using the same
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The present invention provides novel coordination complexes, methods for synthesizing and identifying coordination complexes using combinatorial techniques, and assaying for their activity. In certain embodiments, the subject coordination complexes contain platinum,
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Page/Page column 52
(2010/02/08)
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- Kinetics and mechanism for reduction of halo- and haloam(m)ine platinum(IV) complexes by L-ascorbate
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Reduction of the model platinum(IV) complexes cis-[PtCl4(NH3)2] (1), trans-[PtCl4(NH3)2] (2), trans-[PtCl2(en)2]2+ (3), trans-[PtBr2(NH3)4]2+ (4), [PtCl6]2- (5), and [PtBr6]2- (6) with L-ascorbic acid (H2Asc) in 1.0 M aqueous medium at 25°C in the region 1.75≤pH≤7.20 has been investigated using stopped-flow spectrophotometry. The redox reactions follow the rate law: -d[Pt(IV]/dt=k[H2Asc]tot[Pt(IV)] where k is a pH-dependent second-order rate constant and [H2Asc]tot, the total concentration of ascorbic acid. The pH-dependence of k is attributed to parallel reduction of Pt(IV) by the protolytic species HAsc- and Asc2-. Analysis of the kinetics data reveals that the ascorbate anion Asc2- is up to seven orders of magnitude more reactive than HAsc- while H2Asc is unreactive. Electron transfer from HAsc-/Asc2- to the Pt(IV) compounds is suggested to take place by a mechanism involving a reductive attack on any one of the mutually trans-halide ligands by Asc2- and/or HAsc- forming a halide-bridged activated complex. The rapid reduction of these complexes supports the assumption that ascorbate Asc2- might be an important reductant at physiological conditions for anticancer active Pt(IV) pro-drugs capable of undergoing reductive trans elimination. The parameters ΔH≠ and ΔS≠ for reduction of Pt(IV) with Asc2- have been determined from the study of the temperature dependence of k.
- Lemma, Kelemu,House, Donald A.,Retta, Negussie,Elding, Lars I.
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- Synthesis, characterization, and reactivity of trans-[PtCl(R′R″SO)(A)2]NO3 (R′R″SO = ME2SO, MeBzSO, MePhSO; A = NH3, py, pic). Crystal structure of trans-[PtCl(Me2SO)(py)2]+
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Trans complexes such as trans-[PtCl2(NH3)2] have historically been considered therapeutically inactive. The use of planar ligands such as pyridine greatly enhances the cytotoxicity of the trans geometry. The complexes trans-[PtCl(R′R″SO)(A)2]NO3 (R′R″SO = substituted sulfoxides such as dimethyl (Me2SO), methyl benzyl (MeBzSO), and methyl phenyl sulfoxide (MePhSO) and A = NH3, pyridine (py) and 4-methylpyridine or picoline (pic)) were prepared for comparison of the chemical reactivity between ammine and pyridine ligands. The X-ray crystal structure determination for trans-[PtCl(Me2SO)(py)2]NO3 confirmed the geometry with S-bound Me2SO. The crystals are orthorhombic, space group P212121, with cell dimensions a = 7.888(2) A, b = 14.740(3) A, c = 15.626(5) A, and Z = 4. The geometry around the platinum atom is square planar with l(Pt-Cl) = 2.304(4) A, l(Pt-S) = 2.218(5) A and l(Pt-N) = 2.03(1) and 2.02(1) A. Bond angles are normal with Cl-Pt-S = 177.9(2)°, Cl-Pt-N1 = 88.0(4)°, Cl-Pt-N2 = 89.3(5)°, S-Pt-N1 = 93.8(4)°, S-Pt-N2 = 88.9(4)°, and N1-Pt-N2 = 177.2(6)°. The intensity data were collected with Mo Kα radiation with a λ = 0.710 69 A. Refinement was by full-matrix least-squares methods to a final R value of 3.80%. Unlike trans-[PtCl2(NH3)2], trans-[PtCl2(A)2] (A = py or pic) complexes do not react with Me2SO. The solvolytic products of cis-[PtCl2(A)2] (A = py or pic) were characterized. Studies of displacement of the sulfoxide by chloride were performed using HPLC. The sulfoxide was displaced faster for the pyridine complex relative to the ammine complex. Chemical studies comparing the reactivity of trans-[PtCl(R′R″SO)(amine)2]NO3 with a model nucleotide, guanosine 5′-monophosphate (GMP), showed that the reaction gave two principal products: the species [Pt(R′R″SO)(amine)2(N7-GMP)], which reacts with a second equivalent of GMP, forming [Pt(amine)2(N7- GMP)2]. The reaction pathways were different, however, for the pyridine complexes in comparison to the NH3 species, with sulfoxide displacement again being significantly faster for the pyridine case.
- Fontes,Oskarsson,Loevqvist,Farrell
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p. 1745 - 1750
(2008/10/08)
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- Uracil quartet formation through non-covalent interaction with a neutral metal ammine complex
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Cocrystallization of 1-methyluracil (Hmura) and trans[PtCl4(NH3)2] yields an adduct of composition [PtCl4(NH3)2·2 Hmura with two types of uracil quartets, one of which is relevant to that formed in tetraplex RNA.
- Witkowski, Holger,Freisinger, Eva,Lippert, Bernhard
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p. 1315 - 1316
(2007/10/03)
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