New Organometallic Tetraphenylethylene⋅Iridium(III) Complexes with Antineoplastic Activity

Iridium(III) complexes have attracted more and more attention in the past few years because of their potential antineoplastic activity. In this study, four Ir^III complexes of the types [(η⁵-Cp^x)Ir(N^N)Cl]PF₆ (complexes 1 and 2 ) and [Ir(Phpy)₂(N^N)]PF₆ (complexes 3 and 4 ) have been synthesized and characterized. They exhibit potential antineoplastic activity towards A549 cells, especially in the case of complex 1 [IC₅₀=(3.56±0.5) μm ], which was nearly six times as effective as cisplatin [(21.31±1.7) μm ]. Additionally, these complexes show some selectivity towards cancer cells over normal cells. They could be transported by serum albumin (binding constants were changed from 0.37×10⁵ to 81.71×10⁵ m ⁻¹). Ir^III complexes 1 and 2 could catalyze the transformation of nicotinamide adenine dinucleotide reduced form (NADH) into NAD⁺ (turnover numbers 43.2, 11.9] and induce the accumulation of reactive oxygen species, thus confirming their antineoplastic mechanism of oxidation, whereas the cyclometalated complexes 3 and 4 were able to target the lysosome [Pearson co-localization coefficient (PCC)=0.73], cause lysosomal damage, and induce apoptosis. Understanding the mechanism of action would help further structure–activity optimization on these Ir^III complexes as emerging cancer therapeutics.     

Metal-Based Catalytic Drug Development for Next-Generation Cancer Therapy

Considering the high increase in mortality caused by cancer in recent years, cancer drugs with novel mechanisms of anticancer action are urgently needed to overcome the drawbacks of platinum-based chemotherapeutics. Recently, in the area of metal-based cancer drug development research, the concept of catalytic cancer drugs has been introduced with organometallic Ru^II, Os^II, Rh^III and Ir^III complexes. These complexes are reported as catalysts for many important biological transformations in cancer cells such as nicotinamide adenine dinucleotide (NAD(P)H) oxidation to NAD⁺, reduction of NAD⁺ to NADH, and reduction of pyruvate to lactate. These unnatural intracellular transformations with catalytic and nontoxic doses of metal complexes are known to severely perturb several important biochemical pathways and could be the antecedent of next-generation catalytic cancer drug development. In this concept, we delineate the prospects of such recently reported organometallic Ru^II, Os^II, Rh^III and Ir^III complexes as future catalytic cancer drugs. This new approach has the potential to deliver new cancer drug candidates.     

Subcellular Localisation of a Quinoline-Containing Fluorescent Cyclometallated IrIII Complex in Plasmodium falciparum

A fluorescent analogue of a previously synthesised N,N-chelated Ir^III complex was prepared by coordination of the organic ligand to an extrinsic bis(2-phenylpyridine)iridium(III) fluorophore. This cyclometallated Ir^III complex in itself displays good, micromolar activity against the chloroquine-sensitive NF54 strain of Plasmodium falciparum. Live-cell confocal microscopy found negligible localisation of the fluorescent complex within the digestive vacuole of the parasite. This eliminated the haem detoxification pathway as a potential mechanism of action. Similarly, no localisation of the complex within the parasitic nucleus was found, thus suggesting that this complex probably does not interfere with the DNA replication process. A substantial saturation of fluorescence from the complex was found near phospholipid structures such as the plasma and nuclear membranes but not in neutral lipid bodies. This indicates that an association with these membranes, or organelles such as the endoplasmic reticulum or branched mitochondrion, could be essential to the efficacies of these types of antimalarial compounds.     

Triazolyl-Functionalized N-Heterocyclic Carbene Half-Sandwich Compounds: Coordination Mode,Reactivity and in vitro Anticancer Activity

We report investigations on the anticancer activity of organometallic [M^II/III(η⁶-p-cymene/η⁵-pentamethylcyclopentadienyl)] (M=Ru, Os, Rh, and Ir) complexes of N-heterocyclic carbenes (NHCs) substituted with a triazolyl moiety. Depending on the precursors, the NHC ligands displayed either mono- or bidentate coordination via the NHC carbon atom or as N,C-donors. The metal complexes were investigated for their stability in aqueous solution, with the interpretation supported by density functional theory calculations, and reactivity to biomolecules. In vitro cytotoxicity studies suggested that the nature of both the metal center and the lipophilicity of the ligand determine the biological properties of this class of compounds. The Ir^III complex 5 d bearing a benzimidazole-derived ligand was the most cytotoxic with an IC₅₀ value of 10 μM against NCI-H460 non-small cell lung carcinoma cells. Cell uptake and distribution studies using X-ray fluorescence microscopy revealed localization of 5 d in the cytoplasm of cancer cells.     

Interactions between Artemisinins and other Antimalarial Drugs in Relation to the Cofactor Model—A Unifying Proposal for Drug Action

Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox‐active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid–methylene blue (MB), N‐benzyl‐1,4‐dihydronicotinamide (BNAH)–MB, BNAH–lumiflavine, BNAH–riboflavin (RF), and NADPH–FAD–E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4‐aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4‐aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via π complex formation between the 4‐aminoquinolines and LMB or the dihydroflavins; this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form π complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme–Fe^III results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme–Fe^III complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme–Fe^III. The quinoline or arylmethanol reenters the DV, and so transfers more heme–Fe^III out of the DV. In this way, the 4‐aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme–Fe^III and thence free Fe^III concentrations in the cytosol. The iron species enter into redox cycles through reduction of Fe^III to Fe^II largely mediated by reduced flavin cofactors and likely also by NAD(P)H–Fre. Generation of ROS through oxidation of Fe^II by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by π complex formation between pairs of lipophilic drugs must adversely influence the pharmacokinetics of each drug. This explains the antagonism between PPQ and MFQ, for example. The basis for the antimalarial activity of RF mirrors that of MB, wherein it participates in redox cycling that involves flavoenzymes or Fre, resulting in attrition of NAD(P)H. The generation of ROS by artemisinins and ensuing Fenton chemistry accommodate the ability of artemisinins to induce membrane damage and to affect the parasite SERCA PfATP6 Ca²⁺ transporter. Thus, the effect exerted by artemisinins is more likely a downstream event involving ROS that will also be modulated by mutations in PfATP6. Such mutations attenuate, but cannot abrogate, antimalarial activities of artemisinins. Overall, parasite resistance to artemisinins arises through enhancement of antioxidant defense mechanisms.     

First-Generation Bispidine Chelators for 213BiIII Radiopharmaceutical Applications

Hepta- and octadentate bispidines (3,7-diazabicyclo[3.3.1]nonane, diaza-adamantane) with acetate, methyl-pyridine, and methyl-picolinate pendant groups at the amine donors of the bispidine platform have been prepared and used to investigate Bi^III coordination chemistry. Crystal structure and solution spectroscopic data (NMR spectroscopy and mass spectrometry) confirm that the rigid and relatively large bispidine cavity with an axially distorted geometry is well suited for Bi^III and in all cases forms nine-coordinate complexes; this is supported by an established hole size and shape analysis. It follows that nonadentate bispidines probably will be more suited as bifunctional chelators for ²¹³Bi^III-based radiopharmaceuticals. However, two isomeric picolinate-/acetate-based heptadentate ligands already show very efficient complexation kinetics with ²¹³Bi^III at ambient temperature and kinetic stability that is comparable with the standard ligands used in this field. The experimentally determined hydrophilicities (log D_7.4 values) show that the Bi^III complexes reported are relatively hydrophilic and well suited for medicinal applications. We also present a very efficient and relatively accurate method to compute charge distributions and hydrophilicities, and this will help to further optimize the systems reported here.     

White Light Emitting Eu<Superscript>III</Superscript> and Tb<Superscript>III</Superscript> Doped Lanthanide Coordination Polymers Based on in Situ Formed Nitrilotriacetic Anion

Three 2D lanthanide coordination polymers of in situ formed nitrilotriacetic anion (NTA^3?) have been hydrothermally synthesized with N-(2-carbamoylmethyl) iminodiacetic acid (H₂ADA) as starting material. The photoluminescence properties as well as the energy-transfer behavior of the resulted coordination polymers are studied in detail and the investigations reveal that both Eu^III and Tb^III complexes show intense emissions characteristic of Eu^III and Tb^III ion under irradiation of 399 nm. Considering the blue-emission of compound Gd^III and the intense emission of Eu^III and Tb^III compounds, we afforded Eu^III and Tb^III doped white light emitting materials by the different combination of the doped Eu^III and Tb^III concentrations.     

Comparing the Antileishmanial Activity of Gold(I) and Gold(III) Compounds in L. amazonensis and L. braziliensis in Vitro

Abstract : A series of mononuclear coordination or organometallic Au^I/Au^III complexes ( 1 – 9 ) have been comparatively studied in vitro for their antileishmanial activity against promastigotes and amastigotes, the clinically relevant parasite form, of Leishmania amazonensis and Leishmania braziliensis. One of the cationic Au^I bis-N-heterocyclic carbenes ( 3 ) has low EC₅₀ values (ca. 4 μM) in promastigotes cells and no toxicity in host macrophages. Together with two other Au^III complexes ( 6 and 7 ), the compound is also extremely effective in intracellular amastigotes from L. amazonensis. Initial mechanistic studies include an evaluation of the gold complexes′ effect on L. amazonensis’ plasma membrane integrity.     

Synthesis of Two New Polyferrocenylsilanes and Magnetic Properties of Their Charge Transfer Complexes

Two polyferrocenylsilanes (PFSs) 1 and 2 with aniline and carbazolyl as side chains have been prepared by treating silyl-chloride functionalized PFS (PFS-Cl) with hydroxyl-ended aniline and carbazole compounds, respectively, and characterized by NMR, FT-IR, elemental analysis (EA), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and cyclic voltammetry (CV). Both of them could be oxidized by iodine and 2,3-dichloro-5,6-dicyanoquinone (DDQ) to form complexes. PFS 1 could be oxidized by tetracyanoethylene (TCNE) too. The complexes are characterized by FT-IR, EA, Iron-57 Mössbauer spectroscopy. All of them are partially oxidized by the oxidants and both Fe^II and Fe^III coexist in the complexes. Magnetic property measurement by superconducting quantum interference device (SQUID) shows their paramagnetic properties with somewhat antiferromagnetic interaction. Results show that the joint type between PFS backbone and the electron-rich side groups has less direct effect on the exhibition of ferromagnetic interaction in their complexes.     

Magnetic behavior of polycarbosilazane ?FeII, ?FeIII and mixed‐valence ?FeII–III chloride metallopolymers

Fe^II, Fe^III and mixed‐valence Fe^II–III chlorides were reacted with poly[N,N′‐bis(dimethylsilyl)ethylenedi‐ amine], [? Si(CH₃)₂NHCH₂CH₂NH? ]_n, to form the corresponding Fe‐polycarbosilazane macromolecular complexes. The average chain–chain spacing in these materials was estimated from X‐ray diffraction data and found to be 6.94, 7.29, 7.30 and 7.45 Å in metal‐free and Fe^II? , Fe^III? and Fe^II–III‐containing polycarbosilazanes, respectively. This demonstrates that Fe^II, Fe^III and Fe^II–III chlorides are encapsulated between the polycarbosilazane chains. The chain–chain expansions in the divalent Fe^II and trivalent Fe^III chloride macromolecular complexes are comparable, but less than that in the Fe^II–III chloride analog, which suggests that different chain–chain packings exist in the mixed‐valence macromolecular complex. The magnetic properties of the resulting complexes were investigated by measuring the magnetization in magnetic fields up to 8 kOe and in the temperature range from liquid nitrogen temperature to room temperature. Copyright © 2007 Society of Chemical Industry     

PAMAM Dendrimer-Derived Ir/Al2O3 Catalysts: An EXAFS Characterization

Extended X-ray absorption fine structure (EXAFS) spectroscopy was used to characterize several synthesis stages of hydroxyl-terminated generation four (G4OH) PAMAM dendrimer-derived Ir/γ-Al₂O₃ catalyst. The EXAFS results indicate that Ir³⁺ forms complexes with dendrimer functional groups through displacement of two Cl^? ion ligands. These complexes are very stable in solution, and no reduction of Ir³⁺ to Ir nanoparticles or clusters is observed after introduction of reducing agents such as NaBH₄ or H₂. These Ir³⁺-dendrimer complexes remain essentially intact after support impregnation. The formation of 1–2 nm particles occurs when the catalysts are treated with O₂/H₂ or H₂, and the dendrimer-derived catalysts exhibit a lower degree of metal support interaction.     

Isoxazole-Derived Aroylhydrazones and Their Dinuclear Copper(II) Complexes Show Antiproliferative Activity on Breast Cancer Cells with a Potentially Alternative Mechanism Of Action

This paper reports the design, synthesis and cytotoxicity studies of two new isoxazole-derived aroylhydrazone ligands and their dinuclear copper(II) complexes. Compounds were fully characterized by various spectroscopic and analytical techniques. The molecular structures of four derivatives were confirmed by X-ray crystallography. The stability of the ligands and the complexes in aqueous medium was monitored spectroscopically. Both the ligands and the complexes were shown to interact with calf thymus DNA (ct-DNA). Additionally, structures containing a phenol pendant arm were significantly more cytotoxic than those carrying a pendant pyridine substituent, reaching sub-micromolar IC₅₀ values on the triple-negative human breast cancer cell line MDA-MB-231. The metal chelation and transchelation ability of the compounds towards Fe^II, Fe^III and Zn^II ions was explored as a possible mechanism of action of these compounds.     

Nickel(III) and Copper(III) Complexes with 13- and 14-membered Tetra-aza Macrocycles. Ring-size and Medium Effects on the MIII/MII Redox Couple Potentials

The one-electron oxidation of the Ni^II and Cu^II complexes with 13- and 14-membered macrocycles 1 and 2 to produce authentic Ni^III and Cu^III species has been electrochemically investigated and the E_1/2 values associated to the reversible M^III/M^II redox couple have been determined by means of the Differential Pulse Voltammetry technique. The 13-membered ring favours the attainment of the Cu^III state, whereas the 14-membered ring favours the formation of the Ni^III complex. This opposite behaviour is satisfactorily interpreted in terms of size of the metal ions and aperture of the macrocyclic cave. Moreover the effect of the concentration of the inert electrolyte (NaClO₄, 0.1–7.0 M) on the E_1/2(M^III/M^II) values has been investigated: the increase of the NaClO₄ concentration favours the formation of the Cu^III complexes and disfavours the formation of the Ni^III species. This behaviour is ascribed to the destabilization of Ni^III and Cu^II complexes induced by perchlorate ion through the formation of hydrogen bonds with water molecules axially coordinated to the metal ions.     

Synthetic and Spectroscopic Studies of Polymeric Metal Complexes Involving 1,4-[5-Disulphonyl-8-Hydroxyquinoline]piperazine

The polymeric metal complexes of Co^II, Ni^II, Cu^II, Zn^II, Cd^II , Ce^III, La^III and UO₂ ^II with 1,4-[5-disulphonyl-8-hydroxyquinoline]piperazine have been synthesized. It has been found that the ligand coordinates to the metal ion as a bibasic tetradentate chelating agent and can form polymeric metal complexes. The structure of the isolated metal complexes is supported by chemical analysis, thermoanalytical data, and conductivity measurements, as well as uv-visible, ¹H-NMR, and IR spectroscopy. The stoichiometry of these metal complexes is M:L=2:3. A tetrahedral stereochemical configuration is suggested for the polymeric metal complexes with the exception of the Ce^III and La^III complexes, which form six-coordinate polymeric metal complexes.     

Highly efficient field emission from aligned ZnO/TiN core-shell nanorods

Novel polycrystalline TiN coated ZnO core-shell heterostructure nanorods have been prepared on carbon paper substrate via a low-temperature hydrothermal and sputtering process. The core-shell emitters exhibit a highly efficient field-emission performance with a low threshold of electric field ∼0.72 V/μm, and a high emission current density ~16.41 mA/cm², a level that is the highest of ZnO emitters reported to date. The improved field-emission characteristics may be attributed to the unique materials combination of ZnO core and TiN shell, resulting in the conductivity enhancement, emission sites increase, and the work function reduction. Our results demonstrate that ZnO/TiN core-shell emitter will be a distinguished candidate for electronic source devices.     

β-Diketonate versus β-Ketoiminate: The Importance of a Ferrocenyl Moiety in Improving the Anticancer Potency

Herein we present a library of fully characterized β-diketonate and β-ketoiminate compounds that are functionalized with a ferrocenyl moiety. Their cytotoxic potential has been determined by screening against human breast adenocarcinomas (MCF-7 and MDA-MB-231), human colorectal carcinoma p53 wild type (HCT116 p53^+/+) and normal human prostate (PNT2) cell lines. The ferrocenyl β-diketonate compounds are more than 18 times more cytotoxic than the ferrocenyl β-ketoiminate analogues. Against MCF-7, compounds functionalized at the meta position are up to nine times more cytotoxic than when functionalized at the para position. The ferrocenyl β-diketonate compounds have increased selectivity towards MCF-7 and MDA-MB-231, with several complexes having selectivity index (SI) values that are more than nine times (MCF-7) and more than six times (MDA-MB-231) that of carboplatin. The stability of these compounds in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) has been assessed by NMR spectroscopy and mass spectrometry studies, and the compounds show no oxidation of the iron center from Fe^II to Fe^III. Cytotoxicity screening was performed in both DMSO and DMF, with no significant differences observedin their potency.     

Synthesis,characterization and antitumoral activity of new di-iron(III) complexes containing naphthyl groups: Effect of the isomerism on the biological activity

The synthesis, physico-chemical characterization and cytotoxicity of two di-iron(III) complexes toward three human leukemia cell lines (THP-1, U937 and Molt-4) are reported: [(Cl2)FeIII(μ-HL1)₂FeIII(Cl₂)]·3H₂O (1) and [(Cl2)Fe^III(μ-HL2)₂Fe^III(Cl₂)] (2), where HL1 and HL2 are isomers and contain pyridine, phenol, amine and alcohol moieties with a naphthyl pendant unit. These compounds were characterized by a range of physico-chemical methods. Electrochemical studies reveal the maintenance of the dinuclear arrangement in solution, which is supported by ESI(+)-MS studies. Mossbauer spectra consist of a unique doublet indicating equivalent iron centers in the whole sample. The hyperfine parameters are typical of high-spin iron(III). Complex (1) is more active than complex (2), showing an effect of the isomerism on the antitumoral activity. The comparison between these data and those obtained for complexes containing copper and cobalt reveals that the isomerism of the ligand, the nature of the metal centers, the nuclearity and the kind of cell line exert a great influence on the biological activity.     

EPR Relaxation‐Enhancement‐Based Distance Measurements on Orthogonally Spin‐Labeled T4‐Lysozyme

Lanthanide‐induced enhancement of the longitudinal relaxation of nitroxide radicals in combination with orthogonal site‐directed spin labeling is presented as a systematic distance measurement method intended for studies of bio‐macromolecules and bio‐macromolecular complexes. The approach is tested on a water‐soluble protein (T4‐lysozyme) for two different commercially available lanthanide labels, and complemented by previously reported data on a membrane‐inserted polypeptide. Single temperature measurements are shown to be sufficient for reliable distance determination, with an upper measurable distance limit of about 5–6 nm. The extracted averaged distances represent the closest approach in Ln^III–nitroxide distance distributions. Studies of conformational changes and of bio‐macromolecule association‐dissociation are proposed as possible application area of the relaxation‐enhancement‐based distance measurements.     

Recent Advances in the Design of Targeted Iridium(III) Photosensitizers for Photodynamic Therapy

Photodynamic therapy (PDT) is a noninvasive treatment for certain types of cancer, bacterial, fungal and viral infections, and skin diseases. In recent years, adaptation of this treatment so as to achieve more specific targeted cancer therapy in particular has attracted significant attention. We focus herein on the design of novel iridium‐based photosensitizers (PSs) with tunable photophysical and photobiological properties as efficient PDT agents. We highlight the ability of some Ir^III photosensitizers to target specific cellular components, including their activation by one‐ and two‐photon irradiation.     

Binuclear rhodium(III) and iridium(III) monoselenocarboxylates: Synthesis,spectroscopy and structure of an ortho-metallated iridium complex featuring an IrCCC(μ-Se) chelate ring

Monoselenocarboxylate–bridged binuclear complexes of Rh^III and Ir^III, [(Cp1MCl)₂(μ-SeCOAr)₂] (1) (M = Rh or Ir; Cp1 = pentamethylcyclopentadienyl; Ar = Ph, C₆H₄Me–4), have been isolated either by the reaction between [Cp1₂M₂(μ-Cl)₂Cl₂] with KSeCOAr in acetonitrile or by treatment of [Cp1MCl(solvent)₂][PF₆] with KSeCOAr in acetone. The novel binuclear complexes, [Cp1IrCl(μ-SeCOAr)(κ²-SeCOC₆H₃R–)IrCp1] (2) (R = H or Me-4) with ortho-metallation at one of the iridium centres have been isolated following the use of excess AgPF₆. The single crystal structure of [Cp1IrCl(μ-SeCOC₆H₅)(κ²-SeCOC₆H₄–)IrCp1] (2a) exhibits two phenylcarboselenolate moieties situated in syn fashion with respect to the “Ir₂Se₂” plane, one of which leans towards the metal centre in order to undergo ortho-metallation after iridium–chlorine bond dissociation.