Synthesis and in vitro Anticancer Activity of Octahedral Platinum(IV) Complexes with Cyclohexyl‐Functionalized Ethylenediamine‐N,N′‐Diacetate‐Type Ligands

The present study describes the synthesis and anticancer activity of novel octahedral Pt^IV complexes with cyclohexyl functionalized ethylenediamine‐N,N′‐diacetate‐type ligands. Molecular mechanics calculations and density functional theory analysis revealed that s‐cis is the preferred geometry of these Pt^IV complexes with tetradentate‐coordinated (S,S)‐ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell‐cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel Pt^IV complexes against various cancer cell lines (IC₅₀ range: 1.9–8.7 μM ) was higher than that of cisplatin (IC₅₀ range: 10.9–67.0 μM ) and proceeded through completely different mechanisms. Cisplatin induced caspase‐dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new Pt^IV complexes caused rapid, caspase‐independent, oxidative stress‐mediated non‐apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.     

Proteins as Possible Targets for Cytotoxic trans‐Platinum(II) Complexes with Aliphatic Amine Ligands: Further Exceptions to the DNA Paradigm

The reactivity of three cytotoxic trans‐Pt^II complexes bearing aliphatic amine ligands, with transferrin and single‐stranded oligonucleotides as DNA models, was investigated by ESI‐MS and the results obtained are discussed in comparison with cisplatin. Tandem MS studies provided additional information on the preferential Pt binding sites. To determine whether trans‐Pt^II complexes can migrate from a peptide to an oligonucleotide, transfer experiments were also performed using ESI‐MS, and competitive binding of the trans‐Pt^II complexes toward a model peptide and different oligonucleotides was also investigated. Significant differences in the reactivity of the trans complexes with respect to cisplatin were observed. In general, adduct formation with the selected peptide is favored for the trans compounds, whereas cisplatin shows a preference for oligonucleotides, especially if adjacent G–G residues are present. The results are discussed in relation to the possible mechanism of action of the trans‐Pt^II complexes.     

Synthesis and Biological Studies of Pyrazolyl‐Diamine PtII Complexes Containing Polyaromatic DNA‐Binding Groups

New [PtCl(pz*NN)]ⁿ⁺ complexes anchored by pyrazolyl‐diamine (pz*NN) ligands incorporating anthracenyl or acridine orange DNA‐binding groups have been synthesized so as to obtain compounds that would display synergistic effects between platination and intercalation of DNA. Study of their interaction with supercoiled DNA indicated that the anthracenyl‐containing complex L²Pt displays a covalent type of binding, whereas the acridine orange counterpart L³Pt shows a combination of intercalative and covalent binding modes with a strong contribution from the former. L²Pt showed a very strong cytotoxic effect on ovarian carcinoma cell lines A2780 and A2780cisR, which are, respectively, sensitive to and resistant to cisplatin. In these cell lines, L²Pt is nine to 27 times more cytotoxic than cisplatin. In the sensitive cell line, L³Pt showed a cytotoxic activity similar to that of cisplatin, but like L²Pt was able significantly to overcome cisplatin cross‐resistance. Cell‐uptake studies showed that L²Pt accumulates preferentially in the cytoplasm, whereas L³Pt reaches the cell nucleus more easily, as clearly visualized by time‐lapse confocal imaging of live A2870 cells. Altogether, these findings seem to indicate that interaction with biological targets other than DNA might be involved in the mechanism of action of L²Pt because this compound, despite having a weaker ability to target the cell nucleus than L³Pt , as well as an inferior DNA affinity, is nevertheless more cytotoxic. Furthermore, ultrastructural studies of A2870 cells exposed to L²Pt and L³Pt revealed that these complexes induce different alterations in cell morphology, thus indicating the involvement of different modes of action in cell death.     

New Platinum(II) Complexes Affecting Different Biomolecular Targets in Resistant Ovarian Carcinoma Cells

Resistance to platinum-based anticancer drugs represents an important limit for their clinical effectiveness and one of the most important field of investigation in the context of platinum compounds. From our previous studies, Pt^II complexes containing the triphenylphosphino moiety have been emerging as promising agents, showing significant cytotoxicity to resistant ovarian carcinoma cells. Two brominated triphenylphosphino trans-platinum derivatives were prepared and evaluated on human tumor cell lines, sensitive and resistant to cisplatin. The new complexes exert a notable antiproliferative effect on resistant ovarian carcinoma cells, showing a remarkable intracellular accumulation and the ability to interact with different intracellular targets. The interaction with DNA, the collapse of mitochondrial transmembrane potential, and the impairment of intracellular redox state were demonstrated. Moreover, a selectivity towards the selenocysteine of thioredoxin reductase was observed. The mechanism of action is discussed with regard to the resistance phenomenon in ovarian carcinoma cells.     

Bis(dipyridophenazine)(2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid)ruthenium(II) Hexafluorophosphate: A Lesson in Stubbornness

Ruthenium complexes are currently considered to be among the most promising alternatives to platinum anticancer drugs. In this work, thirteen structural analogues and organelle/receptor‐targeting peptide bioconjugates of a cytotoxic bis(dppz)‐Ru^II complex [Ru(dppz)₂(CppH)](PF₆)₂ ( 1 ) were prepared, characterized, and assessed for their cytotoxicity and cellular localization (CppH=2‐(2′‐pyridyl)pyrimidine‐4‐carboxylic acid; dppz=dipyrido[3,2‐a:2′,3′‐c]phenazine). It was observed that structural modifications (lipophilicity, charge, and size‐based) result in the cytotoxic potency of 1 being compromised. Confocal microscopy studies revealed that unlike 1 , the screened complexes/bioconjugates do not have a preferential accumulation in mitochondria. The results of this important structure–activity relationship strongly support our initial hypothesis that accumulation in mitochondria is crucial for 1 to exert its cytotoxic action.     

Synthesis and Characterization of Eu3+‐Doped Transparent Glass–ceramics Containing Nanocrystalline SrIINbIVO3

The glass–ceramics containing a rarely achievable nanocrystalline Sr^IINb^IVO₃ phase in the 53.75SiO₂–18.25K₂O–9Bi₂O₃–9SrO–9Nb₂O₅–0.5CeO₂–0.5Eu₂O₃ (mol%) glass system were prepared by the melt‐quench technique followed by a two‐stage controlled heat treatment. The unusual oxidation state of Nb in Sr^IINb^IVO₃ crystal is 4+ and upon heat treatment of the samples at lower temperature of 500°C for several hours, the glass composition and chemical environment around Nb ions played a key role for the formation of Sr^IINb^IVO₃ in the glass–ceramics. The microstructure of the glass–ceramics was studied using TEM and FESEM. The TEM images advocate 10–40 nm crystallite size of Sr^IINb^IVO₃. FTIR study confirms that all the samples consist of SiO₄, BiO₃, BiO₆, and NbO₆ structural units. The refractive index at different wavelengths was found to vary in the range 1.7105–1.7905 and increase with increase in heat‐treatment time. The luminescence spectra of Eu³⁺‐doped glass and glass–ceramics were recorded at 465 nm excitation wavelength and the luminescence intensity is found to be increased with heat‐treatment time due to increase in crystallinity. The high intensity ratio of ⁵D₀→⁷F₂ to ⁵D₀→⁷F₁ indicates that the Eu³⁺‐doped nanocrystalline Sr^IINb^IVO₃ glass–ceramics are promising candidate materials as red‐light source.     

Coordination of Platinum to α-Synuclein Inhibits Filamentous Aggregation in Solution

Accumulation of filamentous aggregates of α-synuclein (AS) in Lewy bodies and neurites is characteristic of neurodegenerative diseases such as Parkinson's disease. Inhibition of AS fibrillation is helpful for understanding of AS aggregate structure and for developing chemical therapies. Herein, we report that the Pt^II-containing antitumor drug cisplatin suppresses filamentous aggregation of AS in solution. Pt^II thus contrasts strongly with reported transition-metal ions such as Mn^II, Fe^III, and Cu^II, which accelerate AS aggregation. Interaction between Pt^II and the side chains of methionine and histidine residues was essential for inhibition of AS fibrillation. Binding of Pt^II to AS did not change the protein′s overall random coil structure, as indicated by solution-state two-dimensional NMR and circular dichroism spectroscopy; and a solution of the AS ⋅ Pt^II complex remained free of filamentous aggregates. Our results constitute interesting new information about the biological chemistry of metal ions in Parkinson's disease and might open new lines of research into the suppression of filamentous aggregation.     

Terpyridine‐Functionalized TentaGel Microbeads: Synthesis,Metal Chelation and First Sequential Complexation

The functionalization of polystyrene/poly(ethylene glycol) TentaGel® microbeads (d = 20 μm) with 2,2′:6′,2″‐terpyridine units is described resulting in a material with easily accessible ligands which possess an excellent affinity for transition metal ions. The subsequent loading with different metal ions via metal‐to‐ligand complexation yielded the corresponding Co^II, Ni^II, Fe^II, and Cu^II modified beads. The isolated materials were investigated in detail utilizing UV/vis spectroscopy, optical microscopy, atomic absorption spectroscopy (AAS), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Moreover, grafting of free terpyridine moieties via ruthenium(II )/ruthenium(III )‐chemistry onto the beads is demonstrated. This opens‐up new pathways for the selective modification of such microbeads and the preparation of functional materials.

Scheme of the formation of bis‐terpyridine‐metal complexes bound to polystyrene/poly(ethylene glycol) TentaGel® microbeads.     

Copper(II)‐bis‐Histidine Coordination Structure in a Fibrillar Amyloid β‐Peptide Fragment and Model Complexes Revealed by Electron Spin Echo Envelope Modulation Spectroscopy

Truncated and mutated amyloid‐β (Aβ) peptides are models for systematic study—in homogeneous preparations—of the molecular origins of metal ion effects on Aβ aggregation rates, types of aggregate structures formed, and cytotoxicity. The 3D geometry of bis‐histidine imidazole coordination of Cu^II in fibrils of the nonapetide acetyl‐Aβ(13–21)H14A has been determined by powder ¹⁴N electron spin echo envelope modulation (ESEEM) spectroscopy. The method of simulation of the anisotropic combination modulation is described and benchmarked for a Cu^II‐bis‐cis‐imidazole complex of known structure. The revealed bis‐cis coordination mode, and the mutual orientation of the imidazole rings, for Cu^II in Ac‐Aβ(13–21)H14A fibrils are consistent with the proposed β‐sheet structural model and pairwise peptide interaction with Cu^II, with an alternating [‐metal‐vacancy‐]_n pattern, along the N‐terminal edge. Metal coordination does not significantly distort the intra‐β‐strand peptide interactions, which provides a possible explanation for the acceleration of Ac‐Aβ(13–21)H14A fibrillization by Cu^II, through stabilization of the associated state and low‐reorganization integration of β‐strand peptide pair precursors.     

Metallchelate ungesättigter 1,2-Dithioäther

Metal Chelates of Unsaturated 1,2-Dithioethers The dialkyl- and diaralkyldithioethers of ethylenebisthiol (edt) and xylenedithiol form cationic 1:2 chelates with the d⁸-metal ions Ag^I and Cu^I, which have been isolated and characterized. Pd^II- and Pt^II-halides yield neutral mixed ligand complexes of the type Me (L L) X₂ (L L = dithioether, X = halogen). The dibenzyldithioether of edt is cleaved oxidatively by Cu^II and yields dibenzyldisulfide, Cu^I and an unidentified product.     

Preparation electroactive film of (n‐pyrrolyl)1,1‐methane dihydroxamic acid and its derivative containing complexing cavities preformed by entwining ligands on metallic centers

The (N‐pyrrolyl)1,1‐methane dihydroxamic acid have been synthesized from its N‐substituted ester group derivative, then chemically polymerized in the presence of oxidants such as ammonium persulphate and Iron(III) perchlorate for hydroxamic acid and ester groups derivatives, respectively. This compound and its ester group derivative was successfully electropolymerized by a cyclic voltammetry method. New functionalized polypyrrole films containing transition metal complexes have been prepared and studied. The strategy is based on the three‐dimensional template effect of a metal center (Cu^II, Ni^II, Cr^III, Fe^III) able to entwine two and three end functionalized chelating ligand before or after polymerization. The used ligand consists of a methyl dihydroxamic acid bearing one pyrrole nuclei. The rigidity of the polymer matrix is sufficient to allow demetalation of the template center (by CN^? or SCN^?) without collapse of the three‐dimensional structure. Such property is related to the expected complex topology of the material prepared. The organic backbone certainly contains interlocking rings and various network substructures. The polymer matrix thus keeps a little memory of the templating metal used for building it. Fe(III) ion turned out to be the most convenient template during the polymer electrosynthesis and seemed to lead to the most structured network. The various complexes obtained using electrochemical synthesis method display electrochemical properties analogous to those of the corresponding catenate in solution. All complexes in low oxidation states are remarkably stabilized by the entwined and entangled system. The conductivity of these polymers and it metal complexes were measured using four‐probe method. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Encapsulation of Organic Dyes within an Electron‐Deficient Redox Metal‐Organic Tetrahedron for Photocatalytic Proton Reduction

The design of artificial systems that mimic highly evolved and finely tuned natural photosynthetic systems is a subject of intensive research. By incorporating electron‐deficient anthraquinone within the ligand backbone, a redox‐active Ni‐based tetrahedron was developed as a redox vehicle for the construction of an artificial photosynthesis system. The tetrahedron can encapsulate fluorescein within its cavity for light‐driven H₂ evolution, with the turnover number reaching 1200 moles H₂ per mole redox catalyst. This well‐designed supramolecular system displayed a significantly superior activities compared with the reference mononuclear compound or introducing an inactive inhibitor (ATP), which confirmed this enzymatic photocatalytic behaviour.     

Oxidation of Pt(II) to Pt(IV) complex with hydrogen peroxide in glycols

The reaction of cis, cis-[Pt^II(9-fm)(dmpda)] (9-fm=9-fluorenylidenemalonate, dmpda=2,2-dimethyl-1,3-propanediamine) with hydrogen peroxide in ethyleneglycol produces cis,trans,cis-[Pt^IV(9-fm)(OCH₂CH₂OH)(OH)(dmpda)]. Its crystal structure shows that the local geometry around the platinum atom approximates a typical octahedral arrangement with the added OCH₂CH₂OH/OH ligands in trans coordination sites. The molecules are packed in a two-dimensional assembly via van der Waals interactions, where the hydrophobic fluorenyl groups are arranged on both faces of the assembly plate whereas the hydrophilic groups fill up the inner part of the plate. The compound bearing both “inorganic OH” and “organic OH” is a potential precursor for further various functionalizations.     

The Potent Inhibitory Effect of a Naproxen‐Appended Cobalt(III)‐Cyclam Complex on Cancer Stem Cells

We report the potency against cancer stem cells (CSCs) of a new cobalt(III)‐cyclam complex ( 1 ) that bears the nonsteroidal anti‐inflammatory drug, naproxen. The complex displays selective potency for breast CSC‐enriched HMLER‐shEcad cells over breast CSC‐depleted HMLER cells. Additionally, it inhibited the formation of three‐dimensional tumour‐like mammospheres, and reduced their viability to a greater extent than clinically used breast cancer drugs (vinorelbine, cisplatin and paclitaxel). The anti‐mammosphere potency of 1 was enhanced under hypoxia‐mimicking conditions. Detailed mechanistic studies revealed that DNA damage and cyclooxygenase‐2 (COX‐2) inhibition contribute to the cytotoxic mechanism of 1 . To the best of our knowledge, 1 is the first cobalt‐containing compound to show selective potency for CSCs over bulk cancer cells.     

Rational Design of a Ratiometric Fluorescent Probe Based on Arene–Metal‐Ion Contact for Endogenous Hydrogen Sulfide Detection in Living Cells

We report the design and development of a fluorescent Cd^II ion complex that is capable of the ratiometric detection of H₂S in living cells. This probe exploits the metal‐ion‐induced emission red shift resulting from direct contact between the aromatic ring of a fluorophore and a metal ion (i.e., arene–metal‐ion or “AM” contact). The Cd^II complex displays a large emission blue shift upon interaction with H₂S as the Cd^II‐free ligand is released by the formation of cadmium sulfide. Screening of potential ligands and fluorophores led to the discovery of a pyronine‐type probe, 6? Cd^II, that generated a sensitive and rapid ratio value change upon interaction with H₂S, without interference from the glutathione that is abundant in the cell. The membrane‐impermeable 6? Cd^II was successfully translocated into live cells by using an oligo‐arginine peptide and pyrenebutylate as carriers. As such, 6? Cd^II was successfully applied to the ratiometric detection of both exogenous and endogenous H₂S produced by the enzymes in living cells, thus demonstrating the utility of 6? Cd^II in biological fluorescence analysis.     

The Anticancer Activity of Organotelluranes: Potential Role in Integrin Inactivation

Organic Te^IV compounds (organotelluranes) differing in their labile ligands exhibited anti‐integrin activities in vitro and anti‐metastatic properties in vivo. They underwent ligand substitution with l ‐cysteine, as a thiol model compound. Unlike inorganic Te^IV compounds, the organotelluranes did not form a stable complex with cysteine, but rather immediately oxidized it. The organotelluranes inhibited integrin functions, such as adhesion, migration, and metalloproteinase secretion mediation in B16F10 murine melanoma cells. In comparison, a reduced derivative with no labile ligand inhibited adhesion of B16F10 cells to a significantly lower extent, thus pointing to the importance of the labile ligands of the Te^IV atom. One of the organotelluranes inhibited circulating cancer cells in vivo, possibly by integrin inhibition. Our results extend the current knowledge on the reactivity and mechanism of organotelluranes with different labile ligands and highlight their clinical potential.     

Photochemical reductive elimination of [PtIV(NH3)4(NH2)Cl]2 +: Photogeneration of hydrazine

When [Pt^IV(NH₃)₅Cl]^3 + is deprotonated the complex [Pt^IV(NH₃)₄(NH₂)Cl]^2 + is formed. Upon NH₂⁻ → Pt^IV LMCT excitation (λ_irr > 250 nm) a reductive elimination takes place: [Pt^IV(NH₃)₄(NH₂)Cl]^2 + → [Pt^II(NH₃)₃Cl]⁺ + N₂H₄ + H⁺. Since Pt(II) ammine complexes can be reoxidized to Pt(IV) by H₂O₂ it is suggested that in a cyclic process the overall reaction could proceed according to the equation: 2 NH₃ + H₂O₂ → N₂H₄ + 2 H₂O.     

Photoinduced Isomerization and Hepatoxicities of Semaxanib,Sunitinib and Related 3‐Substituted Indolin‐2‐ones

3‐Substituted indolin‐2‐ones are an important class of compounds that display a wide range of biological activities. Sunitinib is an orally available multiple tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration (FDA) for the treatment of renal cell cancer. Sunitinib and a related compound, semaxanib, exist as thermodynamically stable Z isomers, which photoisomerize to E isomers in solution. In this study, 17 3‐substituted indolin‐2‐ones were synthesized, and the kinetics of their photoisomerization were studied by ¹H NMR spectroscopy. The rate constants for photoisomerization ranged from 0.009 to 0.048 h^?1. Selected compounds were tested for cytotoxicity in the TAMH liver cell line. E/Z mixtures of four compounds were also assessed for toxicity in the TAMH and HepG2 cell lines. In some cases, the stereochemically pure drug was more toxic than the E/Z mixtures, but a general statement cannot be made. Our studies show that each stereoisomer could contribute differently to toxicity, suggesting that stereochemical purity issues that could arise from isomerization cannot be ignored.     

Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

Despite the long‐known fact that the facilitative glucose transporter GLUT1 is one of the key players safeguarding the increase in glucose consumption of many tumor entities even under conditions of normal oxygen supply (known as the Warburg effect), only few endeavors have been undertaken to find a GLUT1‐selective small‐molecule inhibitor. Because other transporters of the GLUT1 family are involved in crucial processes, these transporters should not be addressed by such an inhibitor. A high‐throughput screen against a library of ～3 million compounds was performed to find a small molecule with this challenging potency and selectivity profile. The N‐(1H‐pyrazol‐4‐yl)quinoline‐4‐carboxamides were identified as an excellent starting point for further compound optimization. After extensive structure–activity relationship explorations, single‐digit nanomolar inhibitors with a selectivity factor of >100 against GLUT2, GLUT3, and GLUT4 were obtained. The most promising compound, BAY‐876 [N⁴‐[1‐(4‐cyanobenzyl)‐5‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐4‐yl]‐7‐fluoroquinoline‐2,4‐dicarboxamide], showed good metabolic stability in vitro and high oral bioavailability in vivo.     

Incorporation of Core‐Twisted Perylene Bisimide Ligands into a Discrete Cp*Rh‐Based Molecular‐Rectangle via Coordination‐Driven Self‐Assembly

A tetranuclear metallarectangle ( 2 ) derived from dinuclear rhodium(III) building block [Cp*₂Rh₂(μ‐η²‐η²‐C₂O₄)]Cl₂ and imidazole‐based perylene bisimide ditopic ligand ( 1 ) ( 1= 2,9‐bis(4‐(1H‐imidazol‐1‐yl)phenyl)‐5,6,12,13‐tetrachloroanthra‐[2,1,9‐def:6,5,10‐d′e′f′]diisoquinoline‐1,3,8,10(2H,9H)‐tetraone) in presence of silver triflate is reported. The self‐assembled metallarectangle 2 is fully characterized by NMR, ESI‐MS, UV‐vis absorption, fluorescence emission spectroscopy and cyclic voltammetry. The X‐ray diffraction analysis reveals a twisted conformational geometry of metallarectangle 2 caused by essential steric demands of the two side‐by‐side chlorine atoms. In addition, the analyzed structure also elaborates the intermolecular electrostatic interactions between the electron‐deficient diimide moiety of 2 and the electron‐rich planar phenanthrene molecule.