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1.
Platinum(II) anticancer drugs are among the most effective and often used chemotherapeutic drugs. In recent years, there has been increasing interest in exploiting inert platinum(IV) scaffolds as a prodrug strategy to mitigate the limitations of platinum(II) anticancer complexes. In this prodrug strategy, the axial ligands are released concomitantly upon intracellular reduction to the active platinum(II) congener, offering the possibility of conjugating bioactive co-drugs which may synergistically enhance cytotoxicity on cancer cells. Existing techniques of tethering bioactive molecules to the axial positions of platinum(IV) prodrugs suffer from limited scope, poor yields and low reliability. This report explores the applications of current chemoselective ligation chemistries to platinum(IV) anticancer complexes with the aim of addressing the aforementioned limitations. Here, we describe the synthesis of a platinum(IV) complex bearing an aromatic aldehyde functionality and explored the scope of imine ligation with various hydrazide and aminooxy functionalized substrates. As a proof of concept, we tethered a six sequence long peptide mimetic (AMVSEF) of the anti-inflammatory protein, ANXA1. 相似文献
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B. A. Howell P. Chhetri A. Dumitrascu K. N. Stanton 《Journal of Thermal Analysis and Calorimetry》2010,102(2):499-503
Organoplatinum antitumor agents are very effective, broad-spectrum drugs used for the treatment of a variety of cancerous
conditions. The two most prominent of these, Cisplatin [cis-diamminodichloroplatinum(II)] and Carboplatin [diammino(1,1-cyclobutanedicarboxylato)platinum(II)], are large scale commercial
successes. The third, Oxaliplatin [((trans-1,2-diamminocyclohexane)oxalato)platinum(II)], is now commercially available. The administration of all these drugs is accompanied
by severe side effects. For Cisplatin, the most debilitating of these is kidney damage and extreme nausea. Several approaches
to generate drug-release formulations that might mitigate toxic side effects have been explored. Now, platinum(IV) compounds
which are more inert than platinum(II) compounds, and consequently less toxic, but which may be reduced to platinum(II) species
within the cell are being evaluated for effectiveness in the treatment of cancer. The thermal stability of several precursors
to compounds of this kind has been examined by thermogravimetry. In general, these materials lose ligands sequentially to
generate a residue of platinum. This behavior may be generally useful for the characterization of such materials. 相似文献
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Human Serum Albumin Conjugated Nanoparticles for pH and Redox‐Responsive Delivery of a Prodrug of Cisplatin 下载免费PDF全文
Hongdong Shi Qinqin Cheng Siming Yuan Xin Ding Prof. Yangzhong Liu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(46):16547-16554
Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual‐responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the PtIV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt–HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the PtIV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells. 相似文献
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Abramkin S Valiahdi SM Jakupec MA Galanski M Metzler-Nolte N Keppler BK 《Dalton transactions (Cambridge, England : 2003)》2012,41(10):3001-3005
Platinum-based drugs play a crucial role in the fight against cancer. Oxaliplatin, which is used in the treatment of colorectal carcinoma, was the last platinum-based agent to be approved worldwide. However, the efficiency of the therapy is limited for example by a low accumulation of the drug in cancer cells. Cell-penetrating peptides (CPPs) are known to ease the cellular membrane transport and are used as vectors for low-molecular-weight drugs and drug carriers; of them, TAT peptides are the best-studied group. In this work, a TAT-peptide fragment (YGRKKRRQRRR) was for the first time conjugated to a platinum(IV) analog of oxaliplatin as a vehicle for membrane penetration. Solid-phase peptide synthesis and subsequent coupling with the platinum complex afforded mono- and difunctionalized conjugates, which were separated by preparative HPLC and characterized by analytical HPLC, ESI-MS, and (1)H NMR spectroscopy. Both conjugates are active in the low micromolar range in CH1 and SW480 human cancer cells, requiring much lower concentrations than the untargeted analogs for equal effects. 相似文献
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Davide Corinti Gilles Frison Barbara Chiavarino Elisabetta Gabano Domenico Osella Maria Elisa Crestoni Simonetta Fornarini 《Angewandte Chemie (International ed. in English)》2020,59(36):15595-15598
Platinum(IV) complexes are extensively studied for their activity against cancer cells as potential substitutes for the widely used platinum(II) drugs. PtIV complexes are kinetically inert and need to be reduced to PtII species to play their pharmacological action, thus acting as prodrugs. The mechanism of the reduction step inside the cell is however still largely unknown. Gas‐phase activation of deprotonated platinum(IV) prodrugs was found to generate products in which platinum has a formal +3 oxidation state. IR multiple photon dissociation spectroscopy is thus used to obtain structural information helping to define the nature of both the platinum atom and the ligands. In particular, comparison of calculations at DFT, MP2 and CCSD levels with experimental results demonstrates that the localization of the radical is about equally shared between the dxz orbital of platinum and the pz of nitrogen on the amino group, the latter acting as a non‐innocent ligand. 相似文献
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Yanpeng Liu Dr. Houzong Yao Dr. Man-Kit Tse Shu Chen Dr. Shek-Man Yiu Prof. Dr. Guangyu Zhu 《欧洲无机化学杂志》2023,26(3):e202200763
Platinum-based complexes are among the most widely utilized cancer therapeutics. Current Pt(II) drugs face some challenges including toxicity and drug resistance. To solve these issues, great efforts have been devoted to developing nonclassical platinum complexes, such as Pt(IV) prodrugs, that act via mechanisms distinct from those of the approved drugs. Compared with active Pt(II) counterparts, Pt(IV) complexes are relatively inert. Although direct interactions between Pt(IV) complexes and nucleotides have been reported, the reaction is slow due to the kinetic inertness of Pt(IV) complexes. Herein, we design and synthesize a Pt(IV) monotrifluoromethyl complex, in which the chloride ligand that is trans to trifluoromethyl ligand is reactive. The Pt(IV) monotrifluoromethyl complex is very stable in water but displays high reactivity towards various substrates including buffer components and 5’-dGMP. The study of reaction mechanism reveals that this Pt(IV) complex reacts with phosphate via SN2 nucleophilic substitution pathway, which is different from Pt(II) drugs. The Pt(IV) monotrifluoromethyl complex is cytotoxic in human ovarian cancer cells. Our work reports an example of a reactive organometallic Pt(IV) complex that can directly interact with nucleophiles and implies its potential as an anticancer agent. 相似文献
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Jianhua Yan Yixuan Zhang Lijuan Zheng Yuwei Wu Ting Wang Ting Jiang Xiaoqin Liu Dongming Peng Yanfei Liu Zhenbao Liu 《中国化学快报》2022,33(2):767-772
The drug resistance of chemotherapy is a major challenge to overcome for antineoplastic agents and the reverse of drug resistant is essential for cancer therapy. Herein, we developed a drug delivery system which can simultaneously detect/reverse the drug resistance and perform synergetic treatment of cancer. In this work, we integrated cyanine5(Cy5) modified mi RNA(let-7 i)(Cy5-mi RNA) and platinum onto nano-graphene oxide(NGO)(30-50 nm) platform to achieve simultaneously detection/reversion of ... 相似文献
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Ariadna Lázaro Cristina Balcells Dr. Josefina Quirante Prof. Josefa Badia Prof. Laura Baldomà Dr. Jas S. Ward Prof. Kari Rissanen Dr. Mercè Font-Bardia Prof. Laura Rodríguez Dr. Margarita Crespo Prof. Marta Cascante 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(9):1947-1952
Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N′)PtIV compounds derived from amine–imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs. 相似文献
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Dhar S Liu Z Thomale J Dai H Lippard SJ 《Journal of the American Chemical Society》2008,130(34):11467-11476
Most low-molecular-weight platinum anticancer drugs have short blood circulation times that are reflected in their reduced tumor uptake and intracellular DNA binding. A platinum(IV) complex of the formula c, c, t-[Pt(NH 3) 2Cl 2(O 2CCH 2CH 2CO 2H)(O 2CCH 2CH 2CONH-PEG-FA)] ( 1), containing a folate derivative (FA) at an axial position, was prepared and characterized. Folic acid offers a means of targeting human cells that highly overexpress the folate receptor (FR). Compound 1 was attached to the surface of an amine-functionalized single-walled carbon nanotube (SWNT-PL-PEG-NH 2) through multiple amide linkages to use the SWNTs as a "longboat delivery system" for the platinum warhead, carrying it to the tumor cell and releasing cisplatin upon intracellular reduction of Pt(IV) to Pt(II). The ability of SWNT tethered 1 to destroy selectively FR(+) vs FR(-) cells demonstrated its ability to target tumor cells that overexpress the FR on their surface. That the SWNTs deliver the folate-bearing Pt(IV) cargos into FR(+) cancer cells by endocytosis was demonstrated by the localization of fluorophore-labeled SWNTs using fluorescence microscopy. Once inside the cell, cisplatin, formed upon reductive release from the longboat oars, enters the nucleus and reacts with its target nuclear DNA, as determined by platinum atomic absorption spectroscopy of cell extracts. Formation of the major cisplatin 1,2-intrastrand d(GpG) cross-links on the nuclear DNA was demonstrated by use of a monoclonal antibody specific for this adduct. The SWNT-tethered compound 1 is the first construct in which both the targeting and delivery moieties have been incorporated into the same molecule; it is also the first demonstration that intracellular reduction of a Pt(IV) prodrug leads to the cis-{Pt((NH 3) 2} 1,2-intrastrand d(GpG) cross-link in nuclear DNA. 相似文献
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Dr. Qian Cao Dan-Jie Zhou Zheng-Yin Pan Dr. Gang-Gang Yang Hang Zhang Prof. Liang-Nian Ji Prof. Zong-Wan Mao 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(42):18715-18721
Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)-targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA-MB-231 tumors both in vitro and in vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti-metastasis and anti-angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70–90 times higher than those of cisplatin/oxaliplatin with effectively alleviated side-effects. 相似文献
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Ying Wang Linxiang Cai Hui Li Hanhua Chen Tao Yang Yehong Tan Zijian Guo Xiaoyong Wang 《Angewandte Chemie (International ed. in English)》2023,62(42):e202309043
Drug resistance is a serious challenge for platinum anticancer drugs. Platinum complexes may get over the drug resistance via a distinct mechanism of action. Cholesterol is a key factor contributing to the drug resistance. Inhibiting cellular cholesterol synthesis and uptake provides an alternative strategy for cancer treatment. Platinum(IV) complexes FP and DFP with fenofibric acid as axial ligand(s) were designed to combat the drug resistance through regulating cholesterol metabolism besides damaging DNA. In addition to producing reactive oxygen species and active platinum(II) species to damage DNA, FP and DFP inhibited cellular cholesterol accumulation, promoted cholesterol efflux, upregulated peroxisome proliferator-activated receptor alpha (PPARα), induced caspase-1 activation and gasdermin D (GSDMD) cleavage, thus leading to both apoptosis and pyroptosis in cancer cells. The reduction of cholesterol significantly relieved the drug resistance of cancer cells. The double-acting mechanism gave the complexes strong anticancer activity in vitro and in vivo, particularly against cisplatin-resistant cancer cells. 相似文献
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Westendorf AF Bodtke A Bednarski PJ 《Dalton transactions (Cambridge, England : 2003)》2011,40(19):5342-5351
Light-activation of metal ion complexes to cytotoxic species is of interest due to the potential use in anticancer therapy. Two platinum complexes, trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)] (3) and trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] (4) were irradiated with either UV (λ = 366 nm) or white fluorescent light and the various photochemical and photobiological phenomena were characterized. HPLC coupled to UV/Vis and MS detection was used to identify photochemical species resulting from irradiation of 4 with UV and white light. These studies showed that various Pt(IV) and Pt(II) products formed during the photolysis. The mass spectra of Pt(IV) complexes showed Pt ions in both the positive as well as the negative mode while Pt(II) complexes resulted in only positively charged Pt(III) ions. Since cellular DNA is considered to be a key target for platinum antitumor drugs, the irreversible platination of calf thymus DNA by the photoactivated Pt(IV) complexes was followed by Atomic Adsorption spectrometry (AAS). The effect of adding chloride or biological reducing agents glutathione (GSH) and ascorbic acid on the rates of DNA platination where also studied. Upon activation by light, both compounds show similar binding behaviour to DNA, but the rates of DNA platination for 3 were faster than for 4. Both chloride and GSH protected DNA from platination by the photoactivated compounds; consistent with the trapping of reactive aqua-Pt species. The presence of ascorbate increased the level of platinum bound to DNA for photoactivated 4 but not for 3. Without photoactivation, little or no DNA platination was observed, either with or without ascorbate or GSH. Cytotoxicity studies with two human cancer cell lines underline the photochemotherapeutic potential of these compounds. Striking is the increase in cytotoxic potency with the replacement of an ammine by a pyridine ligand. 相似文献
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Bednarski PJ Grünert R Zielzki M Wellner A Mackay FS Sadler PJ 《Chemistry & biology》2006,13(1):61-67
A possible way to avoid dose-limiting side effects of platinum anticancer drugs is to employ light to cause photochemical changes in nontoxic platinum prodrugs that release active antitumor agents. This strategy could be used in the treatment of localized cancers accessible to irradiation (e.g., bladder, lung, esophagus, and skin). We report here that nontoxic photolabile diam(m)ino platinum(IV) diazido complexes inhibit the growth of human bladder cancer cells upon irradiation with light, and are non-crossresistant to cisplatin. Their rate of photolysis closely parallels that of DNA platination, indicating that the photolysis products interact directly, and rapidly, with DNA. Photoactivation results in a dramatic shrinking of the cancer cells, loss of adhesion, packing of nuclear material, and eventual disintegration of their nuclei, indicating a different mechanism of action from cisplatin. 相似文献
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Zuojie Li Yan Chen Zhifang Liu Qingpeng Wang Yanna Zhao Jinjian Wei Min Liu Zhengping Wang Dacheng Li Jun Han 《Monatshefte für Chemie / Chemical Monthly》2020,151(3):353-367
Naphthalimide has emerged as an interesting DNA intercalator and possessed attracting antitumor properties. In this context, naphthalimide group was linked to platinum(IV) core to construct a series of new mono naphthalimide platinum(IV) derivatives. The title compounds exert effective antitumor activities to the tested tumor cells lines in vitro, especially the one with propionyl chain displays comparable or even better bioactivities than platinum(II) reference drugs cisplatin and oxaliplatin. Moreover, the mono naphthalimide platinum(IV) derivative displays comparable tumor growth inhibitory competence against CT26 xenograft tumors in BALB/c mice in vivo without severe toxic effects in contrast to oxaliplatin. A dual DNA damage mechanism was proven for the title complex. Both naphthalimide ligand and the liberated platinum(II) moiety could generate DNA lesions to tumor cells synergistically and active the apoptotic pathway by up-regulating the expression of caspase 9 and caspase 3. Meanwhile, the conversion of platinum(II) drug into tetravalent form by incorporating naphthalimide moiety increases the uptake of platinum in whole cells and DNA remarkably. All these facts might be the factors for the title platinum(IV) complexes to overcome platinum(II) drug resistance. Additionally, the mono naphthalimide platinum(IV) complex could interact with human serum albumin by hydrogen bond and van der Waals force which would further influence their storage, transport and bioactivities. 相似文献
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Alexander Kastner Hemma Schueffl Patrick A. Yassemipour Bernhard K. Keppler Petra Heffeter Christian R. Kowol 《Angewandte Chemie (International ed. in English)》2023,62(46):e202311468
Platinum(IV) prodrugs are highly interesting alternatives to platinum(II) anticancer therapeutics due to their increased tumor selectivity and reduced side effects. In contrast to the established theory, we recently observed that the equatorial ligand(s) of e.g. oxaliplatin(IV) complexes can be hydrolyzed with formation of [(DACH)Pt(OHeq)2(OAcax)2]. In the work presented here, we investigated the reactivity and synthetic usability of this complex to be exploited as a precursor for the development of novel platinum(IV) complexes, not able to be synthesized by conventional protocols. Indeed, we could substitute the equatorial hydroxido ligand(s) e.g. by one or two monodentate biotin ligands (which would be oxidized under standard methods). The formed complexes turned out to be very stable with slow ligand release after reduction, ideal for long-circulating tumor-targeting strategies. Therefore, two platinum(IV) complexes with equatorial maleimides, capable of exploiting serum albumin as a natural nanocarrier, were synthesized as well. The complexes showed massively prolonged plasma half-life and distinctly improved anticancer activity in vivo compared to oxaliplatin. Taken together, the newly developed synthetic platform allows the simple and specific insertion of equatorial ligands into platinum(IV) complexes. This will enable the attachment of three different (bioactive) moieties generating targeted triple-action platinum(IV) prodrugs within one single platinum complex. 相似文献
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A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin 下载免费PDF全文
Dr. Evyenia Shaili Marta Fernández‐Giménez Savina Rodríguez‐Astor Albert Gandioso Lluís Sandín Carlos García‐Vélez Dr. Anna Massaguer Dr. Guy J. Clarkson Dr. Julie A. Woods Prof. Peter J. Sadler Dr. Vicente Marchán 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(50):18474-18486
A photoactivatable platinum(IV) complex, trans,trans,trans‐[Pt(N3)2(OH)(succ)(py)2] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum‐rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro‐drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X‐ray crystallography. Photoactivation of the platinum–guanidinoneomycin conjugate in the presence of 5′‐guanosine monophosphate (5′‐GMP) led to the formation of trans‐[Pt(N3)(py)2(5′‐GMP)]+, as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3(py)2}+ to guanine nucleobases in a short single‐stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro‐drug in two cancer cell lines, particularly in SK‐MEL‐28 cells. Notably, the higher phototoxicity of the conjugate in SK‐MEL‐28 cells than in DU‐145 cells suggests a degree of selectivity towards the malignant melanoma cell line. 相似文献
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Prof. Jana Kasparkova Dr. Hana Kostrhunova Dr. Olga Novakova Dr. Radka Křikavová Dr. Ján Vančo Prof. Zdeněk Trávníček Prof. Viktor Brabec 《Angewandte Chemie (International ed. in English)》2015,54(48):14478-14482
We report toxic effects of a photoactivatable platinum(IV) complex conjugated with suberoyl‐bis‐hydroxamic acid in tumor cells. The conjugate exerts, after photoactivation, two functions: activity as both a platinum(II) anticancer drug and histone deacetylase (HDAC) inhibitor in cancer cells. This approach relies on the use of a PtIV pro‐drug, acting by two independent mechanisms of biological action in a cooperative manner, which can be selectively photoactivated to a cytotoxic species in and around a tumor, thereby increasing selectivity towards cancer cells. These results suggest that this strategy is a valuable route to design new platinum agents with higher efficacy for photodynamic anticancer chemotherapy. 相似文献
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Hall MD Foran GJ Zhang M Beale PJ Hambley TW 《Journal of the American Chemical Society》2003,125(25):7524-7525
Here we describe the use of X-ray absorption near edge spectroscopy (XANES) to provide information about the relative proportions of platinum(II) and platinum(IV) complexes by analyzing the XANES edge height. The intracellular reduction of platinum(IV) complexes in cancer cells has been observed directly, and the proportion of reduction after 2 h was found to correlate with the reduction potentials of the complexes. 相似文献