- Nanoscale Coordination Polymers Codeliver Carboplatin and Gemcitabine for Highly Effective Treatment of Platinum-Resistant Ovarian Cancer
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Due to the ability of ovarian cancer (OCa) to acquire drug resistance, it has been difficult to develop efficient and safe chemotherapy for OCa. Here, we examined the therapeutic use of a new self-assembled core-shell nanoscale coordination polymer nanoparticle (NCP-Carbo/GMP) that delivers high loadings of carboplatin (28.0 ± 2.6 wt %) and gemcitabine monophosphate (8.6 ± 1.5 wt %). A strong synergistic effect was observed between carboplatin and gemcitabine against platinum-resistant OCa cells, SKOV-3 and A2780/CDPP, in vitro. The coadministration of carboplatin and gemcitabine in the NCP led to prolonged blood circulation half-life (11.8 ± 4.8 h) and improved tumor uptake of the drugs (10.2 ± 4.4% ID/g at 24 h), resulting in 71% regression and 80% growth inhibition of SKOV-3 and A2780/CDDP tumors, respectively. Our findings demonstrate that NCP particles provide great potential for the codelivery of multiple chemotherapeutics for treating drug-resistant cancer.
- Poon, Christopher,Duan, Xiaopin,Chan, Christina,Han, Wenbo,Lin, Wenbin
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- Synthesis of monofunctional platinum(iv) carboxylate precursors for use in Pt(iv)-peptide bioconjugates
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Herein we present platinum(iv) bioconjugates with polyarginine peptides as prospective prodrug delivery systems. Asymmetrical platinum(iv) complexes 3 were obtained via oxidation of parent platinum(ii) complexes 2 with N-bromosuccinimide (NBS) in the presence of succinic anhydride. The combination of these two oxidation reagents furnishes the platinum(iv) environment with two different axial ligands, one of which bears a free carboxylic acid. All platinum(ii) and (iv) compounds were characterized by FT-IR, ESI-MS, HPLC, 1H-, 13C- and 195Pt-NMR. Standard solid-phase peptide chemistry was used for the synthesis of polyarginine (R9) peptides. Coupling of the platinum complexes with peptides N-terminally afforded peptide monoconjugates, which were purified by semi-preparative HPLC and characterized by analytical HPLC and ESI-MS. Platinum(iv)-peptide bioconjugates as well as platinum(ii) and platinum(iv) complexes were tested as cytotoxic agents against two different human cancer cell lines (MCF-7, HepG2) and normal human fibroblasts cell lines (GM5657T). Preliminary in vitro data showed that all platinum(iv) complexes exhibit lower activity than their platinum(ii) precursors towards most cell lines. Interestingly, in the case of HepG2 cells, the Pt(iv)-(R)9-G-A-L bioconjugate (4a) showed even higher activity compared to the non-targeting platinum(iv) parent compound.
- ?mi?owicz, Dariusz,Metzler-Nolte, Nils
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- An intramolecular photoswitch can significantly promote photoactivation of Pt(iv) prodrugs
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Selective activation of prodrugs at diseased tissue through bioorthogonal catalysis represents an attractive strategy for precision cancer treatment. Achieving efficient prodrug photoactivation in cancer cells, however, remains challenging. Herein, we report two Pt(iv) complexes, designated as rhodaplatins {rhodaplatin 1, [Pt(CBDCA-O,O′)(NH3)2(RhB)OH]; rhodaplatin 2, [Pt(DACH)ox(RhB)(OH)], where CBDCA is cyclobutane-1,1-dicarboxylate, RhB is rhodamine B, DACH is (1R,2R)-1,2-diaminocyclohexane, and ox is oxalate}, that bear an internal photoswitch to realize efficient accumulation, significant co-localization, and subsequent effective photoactivation in cancer cells. Compared with the conventional platform of external photocatalyst plus substrate , rhodaplatins presented up to 4.8 × 104-fold increased photoconversion efficiency in converting inert Pt(iv) prodrugs to active Pt(ii) species under physiological conditions, due to the increased proximity and covalent bond between the photoswitch and Pt(iv) substrate. As a result, rhodaplatins displayed increased photocytotoxicity compared with a mixture of RhB and conventional Pt(iv) compound in cancer cells including Pt-resistant ones. Intriguingly, rhodaplatin 2 efficiently accumulated in the mitochondria and induced apoptosis without causing genomic DNA damage to overcome drug resistance. This work presents a new approach to develop highly effective prodrugs containing intramolecular photoswitches for potential medical applications. This journal is
- Chen, Shu,Deng, Zhiqin,Hirao, Hajime,Li, Cai,Wang, Zhigang,Xu, Zoufeng,Yao, Houzong,Zhou, Qiyuan,Zhu, Guangyu
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- BODI-Pt, a Green-Light-Activatable and Carboplatin-Based Platinum(IV) Anticancer Prodrug with Enhanced Activation and Cytotoxicity
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Platinum drugs are widely used in clinics to treat various types of cancer. However, a number of severe side effects induced by the nonspecific binding of platinum drugs to normal tissues limit their clinical use. The conversion of platinum(II) drugs into more inert platinum(IV) derivatives is a promising strategy to solve this problem. Some platinum(IV) prodrugs, such as carboplatin-based tetracarboxylatoplatinum(IV) prodrugs, are not easily reduced to active platinum(II) species, leading to low cytotoxicity in vitro. In this study, we report the design and synthesis of a carboplatin-based platinum(IV) prodrug functionalized with a boron dipyrromethene (bodipy) ligand at the axial position, and the ligand acts as a photoabsorber to photoactivate the platinum(IV) prodrug. This compound, designated as BODI-Pt, is highly stable in the dark but quickly activated under irradiation to release carboplatin and the axial ligands. A cytotoxic study reveals that BODI-Pt is effective under irradiation, with cytotoxicity 11 times higher than that in the dark and 39 times higher than that of carboplatin in MCF-7 cells. Moreover, BODI-Pt has been proven to kill cancer cells by binding to the genomic DNA, arresting the cell cycle at the G2/M phase, inducing oncosis, and generating ROS upon irradiation. In summary, we report a green-light-activatable and carboplatin-based Pt(IV) prodrug with improved cytotoxicity against cancer cells, and our strategy can be used as a promising way to effectively activate carboplatin-based platinum(IV) prodrugs.
- Chen, Shu,Deng, Zhiqin,Matsuda, Yudai,Tse, Man-Kit,Yao, Houzong,Zhu, Guangyu
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supporting information
(2020/09/02)
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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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- 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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supporting information
p. 3143 - 3147
(2018/03/13)
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- MONOMALEIMIDE-FUNCTIONALIZED PLATINUM COMPOUNDS FOR CANCER THERAPY
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The present invention relates to novel monomaleimide-functionalized platinum compounds of formula (I), including in particular novel monomaleimide-functionalized oxaliplatin and carboplatin derivatives, as well as their use as medicaments, particularly for the treatment or prevention of cancer.
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Page/Page column 73
(2017/07/06)
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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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- DNA binding studies of a series of cis-[Pt(Am)2X2] complexes (Am = inert amine, X = labile carboxylato ligand)
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A series of platinum(II) complexes of formulae cis-[Pt(Am) 2X2] (where Am represents an inert amine and X a labile (carboxylato) ligand) have been prepared and characterized by elemental analysis, ESI-MS, IR and 1H NMR spectroscopy. The single-crystal molecular structures were determined for cis-[Pt(opea)(cbdca-2H)], cis-[Pt(hmpy)(cbdca-2H)], cis-[Pt(NH3)2(bzmal-2H)] and cis-[Pt(hmpy)(μ-dcch-2H)2] (where opea is picolylamine, hmpy represents 4-hydroxymethylpyridine, cbdca-2H, is 1,1-cyclobutanedicarboxylate anion, bzmal-2H stands for benzylmalonate anion and dcch-2H is trans-1,2-cyclohexanedicarboxylate anion). The interaction of all compounds with DNA was investigated with different techniques: viscosity measurements and emission fluorescence spectroscopy were used to investigate the changes induced by the binding of the platinum compounds to calf-thymus DNA, while atomic force microscopy and electrophoretic mobility allowed evaluating the potential alterations of pBR322 plasmid DNA. The cytotoxic behavior of the platinum compounds on human leukemia HL-60 tumor cell lines was also examined.
- Escribano, Esther,Font-Bardia, Mercè,Calvet, Teresa,Lorenzo, Julia,Gamez, Patrick,Moreno, Virtudes
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- Novel tetracarboxylatoplatinum(iv) complexes as carboplatin prodrugs
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It is widely accepted that platinum(iv) complexes act as prodrugs and have to be activated by reduction to the respective platinum(ii) analogs. Recently it could be shown that introduction of lipophilic carboxylato ligands in the axial position leads to diaminedichloridoplatinum(iv) compounds with exceptionally high cytotoxicity. With the aim of improving the antiproliferative properties of carboplatin, a series of twenty-one novel Pt(iv) complexes, featuring the equatorial ligand sphere of carboplatin as well as lipophilic axial carboxylato ligands, was synthesized. In depth characterization is based on elemental analysis, ESI-MS, ATR-IR, and multinuclear (1H, 13C, 15N, and 195Pt) NMR spectroscopy. Their cytotoxic activity in four cell lines (CH1, SK-OV-3, SW480, and A549), lipophilicity, electrochemistry and additionally the rate of reduction in the presence of ascorbic acid were investigated. In contrast to analogous diaminedicarboxylatodichloridoplatinum(iv) compounds, the cytotoxicity of novel diaminetetracarboxylato counterparts could not substantially be increased by simply enhancing their lipophilic character. It seems that not only the reduction potential, but also the rate of reduction has a tremendous influence on the cytotoxic properties. This has to be taken into account for the development of novel anticancer platinum(iv) agents.
- Varbanov, Hristo P.,Valiahdi, Seied M.,Kowol, Christian R.,Jakupec, Michael A.,Galanski, Markus,Keppler, Bernhard K.
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p. 14404 - 14415
(2013/04/10)
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- Synthesis, multinuclear magnetic resonance and crystal structures of Pt(II) complexes containing amines and bidentate carboxylate ligands
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A novel synthetic method for the synthesis of the complexes cis-Pt(amine)2R(COO)2 is compared to two other methods involving the use of either barium dicarboxylate or sodium carboxylate. Pt(II) compounds with monodentate and bidentate amines were studied. The reaction involves the use of a silver dicarboxylato complex, which is the intermediate in the new synthetic procedure. The crystal structure of the silver intermediate with the ligand 1,1-cyclobutanedicarboxylate (1,1-CBDCA) was determined by X-ray diffraction. The crystal Ag2(1,1-CBDCA) has a very interesting 3-D extended structure. The complexes cis-Pt(amine)2R(COO)2 were studied in solution by multinuclear (1H, 13C and 195Pt) magnetic resonance spectroscopy, but the solubilities are very low. D2O was found to be the best solvent. In 195Pt NMR, the complexes containing bidentate amines forming five-membered chelates were observed at higher fields than those containing monodentate amines. The resonances of the NH3 compounds were also found at lower fields than the primary amine complexes. All the dicarboxylato ligands form six-membered chelates except 1,2-CBDCA, whose Pt(II) compounds were observed at lower fields than the others. The crystal structures of Pt(en)(1,1-CBDCA), Pt(Meen)(1,1-CBDCA) and Pt(en)(benzylmalonato) were confirmed by X-ray diffraction methods. Several compounds are disordered. The crystals are stabilized by intermolecular hydrogen bonds between the -NH2 groups and the carboxylato O atoms.
- Rochon, Fernande D.,Massarweh, Gassan
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p. 4095 - 4104
(2008/10/09)
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- Synthesis and characterization of Pt(II) complexes with amine and carboxylato ligands. Crystal structure of (1,1-cyclobutanedicarboxylato)di(ethylamine)platinum(II)·H2O
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Two methods for the synthesis of compounds of the type cis-PtA2X2 (A2 = bidentate amine or two monodentate amines and X2 = bidentate or two monodentate carboxylato ligands) were evaluated. The compounds were characterized by multinuclear NMR and IR spectroscopies. The 195PT NMR chemical shifts were in the range - 1615 to - 1976 ppm, the higher field values corresponding to the complexes containing bidentate ligands. The coupling constants 3J(195Pt-1H) are approximately 35 Hz, while the 2J(195Pt-1HN) are about 70 Hz. One coupling constant 2J(195Pt-13C) (53 Hz) was also measured. The crystal structure of the compound, cis-Pt(1,1-cyclobutanedicarboxylato)(C2H5NH2)2·H2O belongs to the P21/n space group with a=9.468(5), b =9.365(4), c = 16.473(7) A?, β = 105.08(3)°, Z = 4 and R1 = 0.0576. The Pt-N bond distances are 1.992(5) and 2.020(5) A?, while the Pt-O bonds are 2.000(4) and 2.015(4) A?. The molecules are held together by intermolecular H-bonds involving the lattice water molecules and the two free carbonyl O atoms and between the amino H atoms and the Pt-bonded C-O groups. (C) 2000 Elsevier Science S.A.
- Rochon, Fernande D.,Gruia, Letitia M.
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p. 193 - 204
(2008/10/08)
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