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1.
Mono‐ and Dinuclear Phosphorescent Rhenium(I) Complexes: Impact of Subcellular Localization on Anticancer Mechanisms 下载免费PDF全文
Rui‐Rong Ye Dr. Cai‐Ping Tan Mu‐He Chen Liang Hao Prof. Liang‐Nian Ji Prof. Zong‐Wan Mao 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(23):7800-7809
Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes ( Re1 and Re2 ), along with their corresponding dinuclear complexes ( Re3 and Re4 ), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1–Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase‐independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase‐independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes. 相似文献
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Organometallic chemistry, biology and medicine: ruthenium arene anticancer complexes 总被引:1,自引:0,他引:1
Yan YK Melchart M Habtemariam A Sadler PJ 《Chemical communications (Cambridge, England)》2005,(38):4764-4776
Our work has shown that certain ruthenium(II) arene complexes exhibit promising anticancer activity in vitro and in vivo. The complexes are stable and water-soluble, and their frameworks provide considerable scope for optimising the design, both in terms of their biological activity and for minimising side-effects by variations in the arene and the other coordinated ligands. Initial studies on amino acids and nucleotides suggest that kinetic and thermodynamic control over a wide spectrum of reactions of Ru(II) arene complexes with biomolecules can be achieved. These Ru(II) arene complexes appear to have an altered profile of biological activity in comparison with metal-based anticancer complexes currently in clinical use or on clinical trial. 相似文献
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Cancer is one of the killers endangering human health and its treatment has always been a focus of the medical community. For anticancer drugs, water-soluble porphyrin and Schiff bases have always been of interest. We report here three Cu(II)-based complexes functionalized by water-soluble cationic porphyrin and hydrazine Schiff base, which were prepared and evaluated for their biological activity. The three Cu(II) complexes all exhibited potent binding affinity to calf thymus DNA, the strongest interaction being between CuP2 and DNA. We studied the cytotoxicity of the complexes and ligands against different types of cancer cells (A549, H-1975, HepG2 and T47D), results showing the ligands are less cytotoxic; therefore, the anticancer activity of the complexes is improved by complexation. Furthermore, the cytotoxicity of ligands and complexes was also evaluated against the normal cell line Hs 578Bst, complexes showing more negligible cytotoxicity than ligand. Moreover, the cellular uptake of these Cu(II) complexes was investigated using the extraction method and results suggested that CuP2 exhibits the best cellular uptake towards H-1975 cells. Interestingly, fluorescence microscopy experiments and flow cytometric analysis (cell cycle) were used to further investigate the potent anticancer activities. 相似文献
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Imine‐N‐Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p‐Cymene Anticancer Complexes: A Structure–Activity Relationship Study 下载免费PDF全文
《化学:亚洲杂志》2018,13(19):2923-2933
A family of novel imine‐N‐heterocyclic carbene ruthenium(II) complexes of the general formula [(η6‐p‐cymene)Ru(C^N)Cl]PF6− (where C^N is an imine‐N‐heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine‐N‐heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD+ is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complex 9 shows the highest anticancer activity in this series against A549 cancer cells (IC50=14.36 μm ), with an approximately 1.5‐fold better activity than the clinical platinum drug cisplatin (IC50=21.30 μm ) in A549 cancer cells. Mechanistic studies reveal that complex 9 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy. 相似文献
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Perihan A. Khalaf-Alla 《应用有机金属化学》2020,34(5):e5628
New expected biologically active complexes for some of the first (Mn (II), Ni (II), Cu (II) and Zn (II)) and second (Rh (III) and Cd (II)) transitional metals rows with N-(2-Aminoethyl)-1,3-propanediamine as a ligand (AEPD)have been synthesized. All synthesized complexes were formed with 1:1 (metal: AEPD) stoichiometry except Ni (II) 1:2 (Ni: AEPD). The compounds were characterized by different analysis tools such as; elemental analysis, Fourier transform infrared (FTIR), 1H-NMR, mass spectra, thermal analysis, electronic spectra, magnetic measurement and molar conductance techniques. AEPD ligand interacted with all metal ions as tridentate ligand by using the nitrogen atoms. On the other hand, density functional theory (DFT) calculations have been performed to confirm the optimized geometrical structures for both AEPD and its complexes. Furthermore, coordination compounds were screened for their potential antibacterial activities against six pathogenic bacteria as well as one kind of fungi in comparison to standard antibiotics by agar well diffusion method. The results show that most of the complexes exhibit antibacterial and antifungal activities against these organisms. Rh (III)-AEPD complex exhibited the strongest antibacterial effect followed by the Cd (II) complex but as antifungal agents Cd (II) was the first and the second was Rh (III). Also, the anticancer activity was screened for these metal complexes against growth of human liver cancer HEPG2 tumor cell line and this inhibition activity of Cd (II) chelate was noticed to be more active with lowest IC50 than that of all other synthesized complexes. Unfortunately, Mn (II) and Rh (III) chelates lacked anticancer activity. The docking active sites interactions were evaluated using the selected protein for anticancer activity. Finally, antioxidant activity was studied. Mn (AEPD) showed maximum activity followed by complex of Rh (III). 相似文献
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Zahra Pouryasin Reza Yousefi S. Masoud Nabavizadeh Mehdi Rashidi Peyman Hamidizadeh Mohammad-Mehdi Alavianmehr Ali Akbar Moosavi-Movahedi 《Applied biochemistry and biotechnology》2014,172(5):2604-2617
The two six-coordinate Pt(IV) complexes, containing bidentate nitrogen donor/methyl ligands with general formula [Pt(X)2Me2(tbu2bpy)], where tbu2bpy = 4,4′-ditert-butyl-2,2′-bipyridine and X = Cl (C1) or Br (C2), serving as the leaving groups were synthesized for evaluation of their anticancer activities and DNA binding properties. To examine anticancer activities of the synthetic complexes, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ethidium bromide/acridine orange (EB/AO) staining method were performed. The binding properties of these complexes to DNA and purine nucleotides were examined, using different spectroscopic techniques. These complexes demonstrated significant anticancer activities against three cancer cell lines Jurkat, K562, and MCF-7. On the basis of the results of EB/AO staining, C1 and C2 were also capable to induce apoptosis in cancer cells. These complexes comprise halide leaving groups, displaying different departure rates; accordingly, they demonstrated slightly dissimilar anticancer activity and significantly different DNA/purine nucleotide binding properties. The results of DNA interaction studies of these complexes suggest a mixed-binding mode, comprising partial intercalation and groove binding. Overall, the results presented herein indicate that the newly synthesized Pt(IV) complexes are promising class of the potential anticancer agents which can be considered as molecular templates in designing novel platinum anticancer drugs. This study also highlights the importance of leaving group in anticancer activity and DNA binding properties of Pt(IV) complexes. 相似文献
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A new kind of nano‐chitosan Schiff‐base Cu complexes with particle sizes of 350 nm were prepared by combination of nano‐chitosan, Cu and Schiff‐base, and characterized by FT‐IR spectra, TEM, DLS and elemental analysis. The modes and mechanism of interaction of the copper complexes with DNA were studied by the fluorescent probe method and electrophoresis analysis. The results suggest that the Cu complexes bound to DNA by electrostatic and intercalation modes. The anticancer activity of the Cu complexes was evaluated by Sulforhodamine B (SRB) assay in vitro. Nano‐chitosan and their Schiff‐base Cu complexes inhibited the growth of the liver cancer cell lines SMMC‐7721 in vitro. The inhibition rate of Schiff‐base Cu complexes was higher than that of nano‐chitosan. Nano‐chitosan combining with Schiff‐base and Cu improved their anticancer activity, which ascribed to the synergistic effect between the chitosan matrix and the planar construction of the Cu complexes. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
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20世纪60年代,美国密执安州立大学Rosenberg发现了顺铂具有抗癌活性,开辟了金属类抗肿瘤药物研究的新领域.经过40余年的研究,已相继成功开发了卡铂、奈达铂、奥沙利铂、舒铂、洛铂和双环铂等铂类抗肿瘤药物.虽然对于铂类抗肿瘤药物研究取得了一定的成绩,但在临床使用过程中也存在一些问题,如其毒副作用和抗药性,限制了其在临床上的进一步广泛应用.为了解决这些问题,科研工作者开始寻找新的金属类抗肿瘤药物以弥补现有铂类抗肿瘤药物的不足.在金属元素中,唯有钯(II)与铂(II)配合物具有相似或相同的结构特征,进而表现出相近或相似的化学性质.因此,继铂类抗肿瘤配合物后,钯(II)配合物作为潜在抗肿瘤药物成为一个诱人的领域.本文综述了近年来钯(II)类抗肿瘤药物的研究进展,并探讨了其构效关系,这对于指导新型钯(II)类抗肿瘤药物的合成具有重要的参考价值. 相似文献
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Saggioro D Rigobello MP Paloschi L Folda A Moggach SA Parsons S Ronconi L Fregona D Bindoli A 《Chemistry & biology》2007,14(10):1128-1139
Although gold compounds are now recognized as promising anticancer agents, so far only gold(I) derivatives have been investigated for this purpose, whereas the use of gold(III) complexes has been hampered by their poor stability under physiological conditions. We have therefore carried out studies on selected gold(III) anticancer agents, showing enhanced stability due to the presence of chelating dithiocarbamato ligands. We found that they induce cancer cell death through both apoptotic and nonapoptotic mechanisms. They also inhibit thioredoxin reductase activity, generate free radicals, modify some mitochondrial functions, and increase ERK1/2 phosphorylation. Based on our results, we propose and discuss a working model suggesting that deregulation of the thioredoxin reductase/thioredoxin redox system is a major mechanism involved in the anticancer activity of the investigated gold(III)-dithiocarbamato complexes. 相似文献
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Maksimoska J Williams DS Atilla-Gokcumen GE Smalley KS Carroll PJ Webster RD Filippakopoulos P Knapp S Herlyn M Meggers E 《Chemistry (Weinheim an der Bergstrasse, Germany)》2008,14(16):4816-4822
In this study, we probe and verify the concept of designing unreactive bioactive metal complexes, in which the metal possesses a purely structural function, by investigating the consequences of replacing ruthenium in a bioactive half-sandwich kinase inhibitor scaffold by its heavier congener osmium. The two isostructural complexes are compared with respect to their anticancer properties in 1205 Lu melanoma cells, activation of the Wnt signaling pathway, IC(50) values against the protein kinases GSK-3beta and Pim-1, and binding modes to the protein kinase Pim-1 by protein crystallography. It was found that the two congeners display almost indistinguishable biological activities, which can be explained by their nearly identical three-dimensional structures and their identical mode of action as protein kinase inhibitors. This is a unique example in which the replacement of a metal in an anticancer scaffold by its heavier homologue does not alter its biological activity. 相似文献
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The frequently severe effects of currently utilized platinum-based complexes have prompted researchers to develop less toxic transition metal based anticancer drugs. Transition metal complexes have recently gained considerable attention as promising anticancer agents due to their efficient drug design and fast optimisation. Some transition metal complexes displayed better anticancer activity than cis-platin. This led to the transition metal complexes for clinical application of chemotherapeutic drugs for cancer therapy. Cytotoxicity of the complexes has been evaluated on the basis of their IC50 values. In this review, we have focussed on recent findings about the anticancer mechanism of action of first row transition metal complexes during the last ten years. 相似文献
16.
Dr. Michael I. Webb Boris Wu Thalia Jang Ryan A. Chard Dr. Edwin W. Y. Wong May Q. Wong Dr. Donald T. T. Yapp Prof. Charles J. Walsby 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(50):17031-17042
A series of pyridine‐based derivatives of the clinically successful RuIII‐based complexes indazolium [trans‐RuCl4(1 H‐indazole)2] (KP1019) and sodium [trans‐RuCl4(1 H‐indazole)2] (KP1339) have been synthesized to probe the effect of hydrophobic interactions with human serum albumin (hsA) on anticancer activity. The solution behavior and protein interactions of the new compounds were characterized by using electron paramagnetic resonance (EPR) and UV/Vis spectroscopy. These studies have revealed that incorporation of hydrophobic substituents at the 4′‐position of the axial pyridine ligand stabilizes non‐coordinate interactions with hsA. As a consequence, direct coordination to the protein is inhibited, which is expected to increase the bioavailability of the complexes, thus potentially leading to improved anticancer activity. By using this approach, the lifetimes of hydrophobic protein interactions were extended from 2 h for the unsubstituted pyridine complex, to more than 24 h for several derivatives. Free complexes were tested for their anticancer activity against the SW480 human colon carcinoma cell line, exhibiting low cytotoxicity. Pre‐treatment with hsA improved the solubility of every compound and led to some changes in activity. Particularly notable was the difference in activity between the methyl‐ and dibenzyl‐functionalized complexes. The former shows reduced activity after incubation with hsA, indicating reduced bioavailability due to protein coordination. The latter exhibits little activity on its own but, following treatment with hsA, exhibited significant cytotoxicity, which is consistent with its ability to form non‐coordinate interactions with the protein. Overall, our studies demonstrate that non‐coordinate interactions with hsA are a viable target for enhancing the activity of RuIII‐based complexes in vivo. 相似文献
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Dr. Alejandro Gutiérrez Dr. Isabel Marzo Prof. Carlos Cativiela Prof. Antonio Laguna Prof. M. Concepción Gimeno 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(31):11088-11095
Several gold(I) complexes with cysteine‐containing dipeptides have been prepared starting from cystine by coupling different amino acids and using several orthogonal protections. The first step is the reaction of cystine, where the sulfur centre is protected as disulfide, with Boc2O in order to protect the amino group, followed by coupling of an amino acid ester; finally the disulfide bridge is broken with mercaptoethanol to afford the dipeptide derivative. Further reaction with [AuCl(PPh3)] gives the gold‐dipeptide‐phosphine species. Starting from these formally gold(I) thiolate–dipeptide phosphine complexes with the general formula [Au(SR)(PR3)] different structural modifications, such as change in the type of the amino protecting group, the type of phosphine, the number of gold(I) atoms per molecule, or the use of a non‐proteinogenic conformationally restricted amino acid ester, were introduced in order to evaluate their influence in the biological activity of the final complexes. The cytotoxic activity, in vitro, of these complexes was evaluated against different tumour human cell lines (A549, MiaPaca2 and Jurkat). The complexes show an outstanding cytotoxic activity with IC50 values in the very low micromolar range. Structure–activity relationship studies from the complexes open the possibility of designing more potent and promising gold(I) anticancer agents. 相似文献
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Anna K. Renfrew Alexander E. Egger Rosario Scopelliti Christian G. Hartinger Paul J. Dyson 《Comptes Rendus Chimie》2010,13(8-9):1144-1150
Metal complexes bearing phosphine ligands are attracting increasing attention for their applications in medicinal chemistry. In particular, organometallic ruthenium-phosphine complexes have been found to exhibit promising antitumour activity. The synthesis, anticancer activity and reactivity of a novel bis-phosphine complex, [Ru(η6-cymene)(PPh2(o-C6H4O)-κ2-P,O)(pta)]Cl (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1.]decane), is presented. The complex appears to exhibit its anticancer effect via a different mechanism to other ruthenium-arene pta complexes with labile co-ligands. 相似文献
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Jahanzaib Arshad Kelvin K. H. Tong Sanam Movassaghi Tilo Shnel Stephen M. F. Jamieson Muhammad Hanif Christian G. Hartinger 《Molecules (Basel, Switzerland)》2021,26(4)
RuII(cym)Cl (cym = η6-p-cymene) complexes of pyridinecarbothioamides have shown potential for development as orally active anticancer metallodrugs, underlined by their high selectivity towards plectin as the molecular target. In order to investigate the impact of the metal center on the anticancer activity and their physicochemical properties, the Os(cym), Rh- and Ir(Cp*) (Cp* = pentamethylcyclopentadienyl) analogues of the most promising and orally active compound plecstatin 2 were prepared and characterized by spectroscopic techniques and X-ray diffraction analysis. Dissolution in aqueous medium results in quick ligand exchange reactions; however, over time no further changes in the 1H NMR spectra were observed. The Rh- and Ir(Cp*) complexes were investigated for their reactions with amino acids, and while they reacted with Cys, no reaction with His was observed. Studies on the in vitro anticancer activity identified the Ru derivatives as the most potent, independent of their halido leaving group, while the Rh derivative was more active than the Ir analogue. This demonstrates that the metal center has a significant impact on the anticancer activity of the compound class. 相似文献
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《Journal of Coordination Chemistry》2012,65(14):2539-2551
Two new heteroleptic Pd(II) dithiocarbamates (1 and 2) have been synthesized by reaction of equimolar quantities of palladium(II) chloride, sodium 4-(3-methoxyphenyl)piperazine-1-carbodithioate, and appropriate substituted triphenylphosphines. The synthesized complexes have been characterized by their physical, spectral (IR, 1H, 13C, and 31P NMR), and X-ray crystallographic data. Complexes 1 and 2 showed square-planar geometry both in solution and solid states. The crystal packing of both complexes revealed similar 3-D-supramolecular networks comprised of 1-D chains. However, the nature and strength of various non-covalent interactions of these networks were slightly different. The DNA interaction studies of the complexes have been carried out by UV–visible spectroscopy to evaluate their anticancer potential. The study suggested intercalative interaction with 2.402 × 104 and 2.713 × 103 M?1 binding constants, respectively. The complexes have also been evaluated for their anticancer activity against HeLa cell line. Both complexes showed higher activity with IC50 values much lower (22.176 and 26.166 μM for 1 and 2, respectively) than the standard cisplatin (78.075 μM). Furthermore, the complexes induced stronger DNA fragmentation as investigated by DNA ladder assay for apoptosis. Our findings suggested that the anticancer action of these compounds stems from their interaction with DNA leading to DNA damage and apoptosis. The excellent activity of 1 and 2 deserves to be a focus for further research and in vivo studies. 相似文献