Platinum complexes as inhibitors of DNA repair protein Ku70 and topoisomerase IIα in cancer cells.

Ku70 protein and topoisomerase IIα (Topo IIα) are promising targets of anticancer drugs, which play critical roles in DNA repair and replication processes. Three platinum(II) complexes, [PtCl(NH3)2(9-(pyridin-2-ylmethyl)-9H-carbazole)]NO3 (OPPC), [PtCl(NH3)2(9-(pyridin-3-ylmethyl)-9H-carbazole)]NO3 (MPPC), and [PtCl(NH3)2(9-(pyridin-4-ylmethyl)-9H-carbazole)]NO3 (PPPC), were designed as inhibitors of Ku70 and Topo IIα. Their antitumor activity and inhibitory efficacy on Ku70 and Topo IIα were investigated on cellular and molecular levels. OPPC exhibited high antiproliferative activity against various cancer cell lines, with acute toxicity to mice being lower than that of cisplatin. Moreover, OPPC could enter cancer cells effectively and cause DNA damage, which was evidenced by the enhanced expression of γ-H2AX, Chk1/2 phosphorylation, p53 and cell cycle arrest. OPPC also downregulated the DNA damage repair protein Ku70 and inhibited the formation of Ku70 foci-the central points or loci of Ku70, which would suppress DNA repair and induce a nonhomologous end joining response in cancer cells. More importantly, these complexes showed inhibition towards Topo IIα; in particular, OPPC was more effective than MPPC and PPPC. In the Topo IIα knockdown cells, Ku70 and Topo IIα were directly associated with the DNA damage and apoptotic response. The molecular docking provided detailed structural insights into the interactions of the complexes with Topo IIα. This study demonstrates that the cytotoxicity of these complexes is associated with the DNA damage and repair pathways mediated by Ku70 and Topo IIα; OPPC is an effective inhibitor of Ku70 and Topo IIα and restrains cancer cells via a mechanism utterly distinct from that of cisplatin.

Functionalized azobenzene platinum(II) complexes as putative anticancer compounds.

The synthesis and characterization of four platinum(II) complexes using azobenzenes conveniently functionalized as ligands has been carried out. The characteristic photochemical behavior of the complexes due to the presence of azobenzene-type ligands and the role of the ligands in the activation of the complexes has been studied. Their promising cytotoxicity observed in HeLa cells prompted us to study the mechanism of action of these complexes as cytostatic agents. The interaction of the compounds with DNA, studied by circular dichroism, revealed a differential activity of the Pt(II) complexes upon irradiation. The intercalation abilities of the complexes as well as their reactivity with common proteins present in the blood stream allows to confirm some of the compounds obtained as good anticancer candidates.

Rational Design of Near-Infrared-Absorbing Pt(II)-Chelated Azadipyrromethene Dyes as a New Generation of Photosensitizers for Synergistic Phototherapy.

Pt(II) photosensitizers are emerging as novel Pt anticancer agents for cancer photodynamic therapy (PDT) to avoid uncontrollable toxicity of cisplatin. However, the application of Pt(II) photosensitizers is limited by tumor hypoxia and the poor penetration depth of excitation light. To overcome these drawbacks, exploiting the next generation of Pt anticancer agents is of urgent need. According to theoretical calculations, novel near-infrared (NIR)-absorbing Pt(II)-chelated azadipyrromethene dyes (PtDP-X, where X = N, C, and S) were designed. Importantly, spin-orbit coupling of the Pt atom could promote the intersystem crossing of a singlet-to-triplet transition for converting oxygen to singlet oxygen (1O2), and the azadipyrromethene skeleton could provide a strong photothermal effect. As expected, PtDP-X exhibited intense NIR absorption and synergistic PDT and photothermal effects with low dark cytotoxicity. Furthermore, water-soluble and biocompatible PtDP-N nanoparticles (PtDP-N NPs) were prepared that achieved effective tumor cell elimination with low side effects under 730 nm light irradiation in vitro and in vivo. This pioneering work could push the exploitation of NIR-absorbing metal-chelated azadipyrromethene dyes, so as to promote the positive evolution of phototherapy agents.

Retinoic Acid-Platinum (II) Complex [RT-Pt(II)] Protects Against Rheumatoid Arthritis in Mice via MEK/Nuclear Factor kappa B (NF-κB) Pathway Downregulation.

BACKGROUND Rheumatoid arthritis (RA) is an inflammatory disorder that is present in approximately 1% of the world's population. This study was aimed to investigate the effect of retinoic acid-platinum (II) complex [RT-Pt(II)] on rheumatoid arthritis (RA) and to explore the mechanism involved. MATERIAL AND METHODS MH7A cell viability was determined by MTT assay and apoptosis was assessed using FACSCalibur flow cytometry. RT-PCR and Western blot assays were used for assessment of mRNA and proteins levels. RESULTS Treatment of rheumatoid arthritis with RT-Pt(II) significantly reduced the levels of IL­1ß, IL-6, IL-8, MMP-1, and MMP-13 in synovial fluid of mice in a dose-dependent manner. The expression of iNOS and COX-2 mRNA and protein in rheumatoid arthritis rats was also significantly inhibited by treatment with RT-Pt(II). The TNF-alpha-induced proliferation of MH7A cells was alleviated by RT-Pt(II) treatment in a concentration-dependent manner. Moreover, RT-Pt(II) treatment induced apoptosis and caused arrest of cell cycle in MH7A cells. The activation of MEK/NF-kappaB pathway was downregulated by RT-Pt(II) treatment in MH7A cells. CONCLUSIONS In summary, the present study demonstrated that RT-Pt(II) inhibits TNF-alpha-induced inflammatory response, suppresses cell viability, and induces apoptosis in rheumatoid arthritis synovial cells. Moreover, RT-Pt(II) exhibited its effect through targeting the MEK/NF-kappaB pathway. Therefore, RT-Pt(II) can be used for the development of treatments for rheumatoid arthritis.

Synthesis of New Cisplatin Derivatives from Bile Acids.

A series of bile acid derived 1,2- and 1,3-diamines as well as their platinum(II) complexes were designed and synthesized in hope to get a highly cytotoxic compound by the combination of two bioactive moieties. All complexes obtained were subjected to cytotoxicity assays in vitro and some hybrid molecules showed an expected activity.

Rashba-like spin splitting along three momentum directions in trigonal layered PtBi2.

Spin-orbit coupling (SOC) has gained much attention for its rich physical phenomena and highly promising applications in spintronic devices. The Rashba-type SOC in systems with inversion symmetry breaking is particularly attractive for spintronics applications since it allows for flexible manipulation of spin current by external electric fields. Here, we report the discovery of a giant anisotropic Rashba-like spin splitting along three momentum directions (3D Rashba-like spin splitting) with a helical spin polarization around the M points in the Brillouin zone of trigonal layered PtBi2. Due to its inversion asymmetry and reduced symmetry at the M point, Rashba-type as well as Dresselhaus-type SOC cooperatively yield a 3D spin splitting with αR ≈ 4.36 eV Å in PtBi2. The experimental realization of 3D Rashba-like spin splitting not only has fundamental interests but also paves the way to the future exploration of a new class of material with unprecedented functionalities for spintronics applications.

Evolution of 1, 3, 5-trisubstituted bipyrazole scaffold based platinum(II) complexes as a biological active agent.

Square planar mononuclear platinum(II) complexes having general formula [Pt(Ln)Cl2], (where, Ln = L1-4) were synthesized with neutral bidentate heterocyclic 1,3,5-trisubstituted bipyrazole based ligands. The synthesized compounds were characterized by physicochemical method such as TGA, molar conductance, micro-elemental analysis and magnetic moment, and spectroscopic method such as, FT-IR, UV-vis, 1H NMR, 13C NMR and mass spectrometry. Biological applications of the compounds were carried out using in vitro brine shrimp lethality bioassay, in vitro antimicrobial study against five different pathogens, and cellular level cytotoxicity against Schizosaccharomyces pombe (S. Pombe) cells. Pt(II) complexes were tested for DNA interaction activities using electronic absorption titration, viscosity measurements study, fluorescence quenching technique and molecular docking assay. Binding constants (Kb) of ligands and complexes were observed in the range of 0.23-1.07 × 105 M-1 and 0.51-3.13 × 105 M-1, respectively. Pt(II) complexes (I-IV) display an excellent binding tendency to biomolecule (DNA) and possess comparatively high binding constant (Kb) values than the ligands. The DNA binding study indicate partial intercalative mode of binding in complex-DNA. The gel electrophoresis activity was carried out to examine DNA nuclease property of pUC19 plasmid DNA.

A Photoactive Platinum(IV) Anticancer Complex Inhibits Thioredoxin-Thioredoxin Reductase System Activity by Induced Oxidization of the Protein.

Thioredoxin (Trx) is an important enzyme in the redox signaling pathway and is usually overexpressed in tumor cells. We demonstrate herein that the photoactive platinum(IV) anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(Py)2] (1) can bind to His, Glu, and Gln residues of Trx upon the irradiation of blue light. More importantly, complex 1 can also induce the oxidation of Met, Trp, and the Cys catalytic sites to form disulfide bonds by generating reactive oxygen species (ROS) upon photoactivation. These eventually lead to inhibition of activity of Trx enzyme and the Trx system and further increase in the cellular ROS level. We speculate that the oxidative damage not only inhibits Trx activity but also greatly contributes to the anticancer action of complex 1.

Synthesis, properties, antitumor and antibacterial activity of new Pt(II) and Pd(II) complexes with 2,2'-dithiobis(benzothiazole) ligand.

Mono- and binuclear Pt(II) and Pd(II) complexes with 2,2'-dithiobis(benzothiazole) (DTBTA) ligand are reported. [Pt(DTBTA)(DMSO)Cl]Cl∙CHCl3 (1) and [Pd2(µ-Cl)2(DTBTA)2]Cl2 (2) have been synthesized and structurally characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy, MS spectrometry and the content of platinum and palladium was determined using a flame atomic spectrometer. Two different coordination modes of 1 and 2 complexes were found; in both complexes, the coordination of Pt(II) and Pd(II) ions involves the N(3) atoms of the ligand but the binuclear complex 2, is a cis-chloro-bridged palladium complex. Evaluation of their in vitro antitumor activity against two human tumor cell lines human breast cancer (MCF-7) and hepatocellular carcinoma (HepG2); and their antimicrobial activity against Escherichia coli and Kokuria rhizophila was performed. Only complex 1 showed a dose- and time-dependent cytotoxic activity against the two tumor cell lines, associated to apoptosis and accumulation of treated cells in G0/G1 phase of cell cycle, while both 1 and 2 exhibited antimicrobial activity with complex 1 much more potent. The study on intracellular uptake in both MCF-7 and HepG2 cell lines revealed that only platinum of complex 1 is present inside the cells, suggesting a different mode of action of the two compounds. This was also in agreement with the results obtained for the antitumor and antibacterial activity.

Design, synthesis and biological evaluation of six dinuclear platinum(II) complexes.

Six dinuclear platinum(II) complexes with a chiral tetradentate ligand, (1R,1'R,2R,2'R)-N1,N1'-(1,4-phenylenebis(methylene))dicyclohexane-1,2-diamine, have been designed, synthesized and characterized. In vitro cytotoxicity evaluation of these metal complexes against human A549, HCT-116, MCF-7 and HepG-2 cell lines have been carried out. All compounds showed antitumor activity to HepG-2, HCT-116 and A549. Particularly, compounds A1 and A2 exhibited significant better activity than other four compounds and A2 even showed comparable cytotoxicity to cisplatin against HepG-2 cell line.

Four mononuclear platinum(II) complexes: synthesis, DNA/BSA binding, DNA cleavage and cytotoxicity.

Four new platinum(II) complexes: PtII L1·H2O (C1, H2 L1 = C20H16N2O2), PtII L2Cl2 (C2, L2 = C22H16N2O2), PtII L3Cl2·H2O (C3, L3 = C20H16N2), PtII L4Cl2·0.4H2O (C4, L4 = C18H14N4) have been synthesized and characterized by using various physico-chemical techniques. The binding interaction of the four platinum(II) complexes C1-C4 with calf thymus (CT)-DNA has been investigated by UV-Vis and fluorescence emission spectrometry. The apparent binding constant (K app) values follow the order: C3 > C1 > C2 > C4. In addition, fluorescence spectrometry of bovine serum albumin (BSA) with the four platinum(II) complexes C1-C4 showed that the quenching mechanism might be a static quenching procedure. For C1-C4, the number of binding sites was about one for BSA and the binding constants follow the order: C3 (7.08 × 105M-1) > C1 (2.82 × 105M-1) > C2 (0.85 × 105M-1) > C4 (0.15 × 105M-1). With the single condition change such as absence of an external agent, the DNA cleavage abilities of C3 exhibit remarkable changes. In addition, the cytotoxicity of C3 in vitro on tumor cells lines (MCF-7, HepG2 and HT29) were examined by MTT and showed better antitumor effects on the tested cells.

Platinum(iv) N-heterocyclic carbene complexes: their synthesis, characterisation and cytotoxic activity.

Platinum(ii) N-heterocyclic carbene complexes have been oxidized by bromine or iodobenzene dichloride to provide the fully characterised corresponding platinum(iv) NHC complexes. Antiproliferative activities of Pt(iv) NHC complexes were assayed against several cancer cell lines and the results were correlated with respect to their stability. Mechanistic investigations revealed that mitochondrial dysfunction and ROS production were associated with the cytotoxic process induced by these compounds.

Synthesis of platinum complexes with 2-(5-perfluoroalkyl-1,2,4-oxadiazol-3yl)-pyridine and 2-(3-perfluoroalkyl-1-methyl-1,2,4-triazole-5yl)-pyridine ligands and their in vitro antitumor activity.

Five new mononuclear Pt(II) complexes with 5-perfluoroalkyl-1,2,4-oxadiazolyl-pyridine and 3-perfluoroalkyl-1,2,4-triazolyl-pyridine ligands are reported. The ligands 2-(5-perfluoroheptyl-1,2,4-oxadiazole-3yl)-pyridine (pfhop), 2-(5-perfluoropropyl)-1,2,4-oxadiazole-3yl)-pyridine (pfpop), 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp) and their complexes [PtCl2(pfhop)2]·1.5 DMSO (2a), [PtCl2(pfpop)2]·1.5 DMSO (3a), [PtCl2(pfhtp)2]·1.5 DMSO (4a), PtCl2(pfhtp) (4b), [PtCl2(pfptp)2]·1.5 DMSO (5a) have been synthesized and structurally characterized. The complexes 2a, 3a, 4a and 5a have the same chemical environment of Pt(II) where PtCl2 moieties coordinate two molecules of ligand via N1 atom of pyridine in the case of pfhop and pfpop, and N2 atom of 1,2,4-triazole in the case of pfhtp and pfptp. For 4b, pfhtp behaves as bidentate ligand, coordinating Pt(II) ion via N4 atom of triazole and N1 atom of pyridine. All complexes have been tested in vitro by 3-(4,5-dimethyl-2-thiazolyl)bromide-2,5-diphenyl-2H-tetrazolium (MTT) test on four tumor cell lines MCF-7 (human breast cancer), HepG2 (human hepatocellular carcinoma), HCT116 (human colorectal carcinoma). Compounds 2a and 4b showed a dose-dependent anti-proliferative effect against the three tumor cell lines whereas did not affect viability of intestinal normal-like differentiated Caco-2 cells. The cell death of HepG2, MCF-7 and HCT116 induced by the compounds, was considered to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and observing the typical apoptotic morphological change by acridine orange (AO)/ethidium bromide (EB) staining.

Selenium-Platinum Coordination Dendrimers with Controlled Anti-Cancer Activity.

Dendrimers are considered as good vectors for drug delivery in cancer treatment. However, most anticancer drugs are conjugated to the peripheral surface of dendrimers, sacrificing the advantages of monodispersity and stability belonging to dendrimers. Furthermore, dendrimers in current studies of cancer treatment are mostly used as vectors for drugs, whereas the anticancer activity of dendrimers on their own is less studied. Here we have prepared monodisperse selenium-platinum coordination dendrimers with a selenium-platinum core buried inside. Structures of the dendrimers were determined by various characterizations. The coordination dendrimers showed controlled anticancer activity by themselves, without loading additional drugs. The in vivo study further demonstrated their anticancer activity and low toxicity to normal tissues.

Combination of Genistein and Cisplatin with Two Designed Monofunctional Platinum Agents in Human Ovarian Tumour Models.

A great amount of research effort has been directed at platinum compounds that bind with DNA differently from cisplatin with the idea that the difference may translate into an altered spectrum of activity. Recently research has also been directed at applying combinations of platinum agents with tumour-active phytochemicals with the aim of providing a means of overcoming platinum resistance in ovarian cancer. Herein we report the synthesis of monofunctional platinum tris(3-hydroxypyridine)chloroplatinum(II) chloride (coded as LH1) and tris(imidazole)chloroplatinum(II) chloride (coded as LH2), and their activity alone and in combination with genistein and cisplatin against human ovarian A2780, cisplatin-resistant A2780(cisR) and picoplatin-resistant A2780(ZD0473R) cancer cell lines. Although both LH1 and LH2 were found to be less active than cisplatin against the tumour models, they produced synergistic outcomes in combination with genistein. Both the level of cellular accumulation of Pt and of Pt-DNA binding resulting from the combination were greater in the A2780(cisR) cell line than in the parental A2780 cell line, irrespective of the sequence of administration. Absence of association between activity of LH1 and LH2 and the level of Pt-DNA binding indicates that the cell death induced by LH1 and LH2 may not be limited to the effect of their binding with DNA.

Site-Selective Trimetallic Heterogeneous Nanostructures for Enhanced Electrocatalytic Performance.

Trimetallic Au/Ag/Pt hetero-nanostructures (AAPHNs) with distinctive, designed morphology are synthesized by galvanic replacement reaction and a site-selective strategy. The three metals present on the surface are shown to act synergistically to enhance the electro-catalytic performance and durability for methanol oxidation. The described structural modification of the nanocomposites increases the range of potential applications to include both the oxygen reduction reaction in fuel cells and photocatalysis of the hydrogen evolution reaction.

Biological evaluation of a novel Herceptin-platinum (II) conjugate for efficient and cancer cell specific delivery.

Platinum-based drugs have been widely used for the treatment of malignant tumors. However, their applications are limited by severe side effects for their lack of selectivity for cancer cells. The development of antibody drug conjugates (ADCs) have provided a platform to reduce drug toxicity and improve drug efficacy. Here we describe a nover conjugate comprising of Herceptin (an anti-HER2 antibody) and platinum drug via a cathepsin B cleavable dipetide for enhancing drug accumulation and HER2-positive cancer cell specific delivery. This conjugate is believed to be cleaved by cathepsin B, leading to a 1,6-elimination reaction and activation of drug release. Herceptin-Pt(II) is evaluated to have approximately loaded with 6.4 moles platinum drugs per mole of antibody. We demonstrate that Herceptin-Pt(II) retain high and selective binding affinity for HER2 protein and HER2-positive SK-BR-3 cancer cells. The in vitro cytotoxicity tests indicate that Herceptin-Pt(II) exhibits much higher cytotoxicity than oxaliplatin against SK-BR-3 cells. More importantly, Herceptin-Pt(II) shows no obvious inhibition against the growth of both MCF-7 and MDA-MB-231 cells, which express lower levels of HER2. Furthermore, compared with free oxaliplatin, Herceptin significantly improved the cellular uptake of platinum drugs in SK-BR-3 cells. In summary, Herceptin-platinum (II) conjugate is a remarkable and potent platform for efficient and cancer cell specific delivery.

Pt-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans: scope and mechanism.

A novel Pt-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans is reported. Mechanistic studies by (13)C-labeling experiments confirm oxidative addition of Pt(II) regioselectively to the least substituted carbon-carbon bond of the cyclopropane to form a platinacyclobutane intermediate. To our knowledge, this is the first alkoxy-substituted platinacyclobutane that has been observed spectroscopically. The scope and a proposed mechanism of this new Pt-catalyzed transformation are described.

Synthesis of a monofunctional platinum compound and its activity alone and in combination with phytochemicals in ovarian tumor models.

Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. In this study, a new monofunctional planaramineplatinum(II) complex, namely tris(8-hydroxyquinoline)monochloroplatinum(II) chloride (coded as LH3), was synthesised and investigated for its activity against human ovarian A2780, cisplatin-resistant A2780 (A2780(cisR)) and ZD0473-resistant A2780 (A2780(ZD0473R)) cancer cell lines, alone and in combination with the phytochemicals curcumin, genistein and resveratrol. Cellular levels of glutathione in A2780 and A2780(cisR) cell lines before and after treatment with LH3 and its combinations with genistein and curcumin were also determined. Interaction of the compounds with salmon sperm DNA, pBR322 plasmid DNA and damage to DNA in A2780 and A2780(cisR) cells due to interaction with LH3-alone and in combination with phytochemicals were also investigated. LH3 was found to be much more active than cisplatin against the resistant tumor models and greatest synergism in activity was observed when combinations of LH3 with genistein and curcumin were administered as a bolus. For combinations of LH3 with the phytochemicals, platinum accumulation and the level of Pt-DNA binding were found to be greater in the resistant A2780(cisR) cell line than in the parental A2780 cell line. Greater activity of LH3 than cisplatin against the resistant ovarian cell lines indicates that it may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy.

Design and biological evaluation of new platinum(II) complexes bearing ligands with DNA-targeting ability.

A novel series of platinum(II) complexes bearing aliphatic amines and ligands with DNA-targeting properties was synthesized to achieve more potent and selective metallodrugs. We developed six new platinum-based drugs, which contain methylamine, 1a-c, and isopropylamine, 2a-c, both in the trans position to a selected targeting ligand: naphthalimide. The activity of the complexes has been evaluated in order to confirm the improvements from our proposed approach, and the complexes demonstrate better cytotoxic activity on cancer cell lines when compared with the ligands and, importantly, with cisplatin. Further studies were performed to assess their subcellular localization and binding mode to DNA.