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.     

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.     

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.     

Aggregation-induced Phosphorescence Enhancement in IrIII Complexes

Transition metal complexes that efficiently emit from an excited state with formally triplet character are an appealing class of compounds. However, they typically suffer from severe quenching, e. g. triplet-triplet annihilation, in aggregated phase that often hampers their use in the solid-state. Nonetheless, an intriguing effect, namely aggregation-induced phosphorescence enhancement, has been sometimes observed, but clear elucidation of the mechanisms underlying this phenomenon is far from trivial. Nowadays, cyclometalated Ir^III emitters play a leading role due to their outstanding features. Aiming at a rationalization of the AIPE effect, an overview of the different classes of Ir^III emitters displaying enhancement of the emission upon aggregation will be herein provided along with their potential applications. Their photophysical properties will be discussed jointly with their X-ray structural analysis. Ir^III complexes represent the largest family of AIPE-active compounds to date.     

Binding and Release of FeIII Complexes from Glucan Particles for the Delivery of T1 MRI Contrast Agents

Yeast-derived β-glucan particles (GPs) are a class of microcarriers under development for the delivery of drugs and imaging agents to immune-system cells for theranostic approaches. However, the encapsulation of hydrophilic imaging agents in the porous GPs is challenging. Here, we show that the unique coordination chemistry of Fe^III-based macrocyclic T₁ MRI contrast agents permits facile encapsulation in GPs. Remarkably, GPs labeled with the simple Fe^III complexes are stable under physiologically relevant conditions, despite the absence of amphiphilic groups. In contrast to the free Fe^III coordination complex, the labeled Fe^III-GPs have lowered T₁ relaxivity and act as a silenced form of the contrast agent. Addition of a fluorescent tag to the Fe^III complex produces a bimodal agent to further enable tracking of the nanoparticles and to monitor release. Treatment of the iron-labeled GPs with a maltol chelator or with mildly acidic conditions releases the intact iron complex and restores enhanced T₁ relaxation of the water protons.     

Preparation and characterization of a series of novel EuIII-complex-polyurethane acrylate materials based on mixed 6-hydroxy-1-naphthoate and 1,10-phenanthroline ligands

Hydroxyl groups in the coordination complex {[Eu( L )₃(phen)]·H₂O}₂ ( L = 6-hydroxy-1-naphthoate and phen = 1,10-phenanthroline) were used to react with  NCO functional groups of isophorone diisocyanate in the presence of dibutyltin dilaurate. A series of new luminescent Eu^III-complex-polyurethane acrylate materials, poly(Eu^III-complex-polyurethane methacrylate (PUA complex)), were prepared through in situ polymerization of polyurethane acrylate macromonomers and the resulting material was characterized by X-ray diffraction, IR spectra, thermogravimetry analysis, dynamic mechanical analysis, and fluorescence spectroscopy. The result indicates that both Eu^III complex and PUA complex can emit characteristic fluorescence of Eu^III ion. Moreover, the emission intensity was enhanced under the same experiment condition when the content of Eu^III complex in the PUA complex was increased. In addition, we have not found the fluorescence quenching in this work even the content of Eu^III complex was increased to 5 wt %. Such rare-earth complex-polyurethane acrylate hybrid materials are suitable for the photoluminescent applications. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

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     

The Mechanism of a Selective Permeation of Ions through “Solvent Polymeric Membranes”

Abstract

The mechanism of diffusion of uranyl nitrate in “solvent polymeric membranes” was investigated. It is suggested that a “carrier” transport mechanism is responsible for the selective permeation of ions or ion pairs through such membranes. The fluidity of the membranes was investigated by proton magnetic resonance and by the “fluorescent probe” technique. Radioactive labeling was used in order to determine the self-diffusion coefficient of dicresylbutylphosphate (DCBP) which serves both as plasticizer and as complexing agent in such membranes. Comparison of its value (～10^?7 cm²/sec) with the limiting value of the diffusion coefficient of uranyl nitrate in such membranes (3.3 × 10^?8 cm²/sec) indicates that the latter diffuses as a (DCBP)₂UO₂(NO₃)₂ complex. It is also suggested that the study of the “solvent polymeric membranes” may help to understand certain properties of biological membranes.     

Benzimidazole-based dendritic nanofiltration membranes

A dendritic-benzimidazole (D-BI) has been prepared using polyphosphoric acid (PPA) as a condensing medium with diaminobenzidine (DAB), 1,3,5-benzene tricarboxylic acid, and isophthalic acid as monomers. The structure of D-BI was ascertained by elemental analysis, FTIR, ¹H NMR, and solid-state ¹³C-NMR. The D-BI was incorporated into polysulphone (PSf) by blending with polyvinylpyrrolidone (PVP K-30) as a macromolecular additive. The membranes were cast by phase inversion technique. The physical properties such as surface morphology and the chemical properties such as contact angle and the performance attributes, such as NOM rejection, salt rejection, and pure water flux were studied. It is imperative that the infusibility of rigid polymeric backbone is overcome by the introduction of polar moieties with no compromise on thermal stability. The membranes displayed substantial increase in thermal stability with D-BI content. The marginal increase in flux has been attributed to the branching and steric effect of D-BI. This is because the introduction of polar group efficiently affords to stabilize the adjacent aromatic rings. The salt rejection shows the order of MgSO₄ ≈ Na₂SO₄ > MgCl₂ > NaCl, which follows that the divalent ions are rejected more than monovalent ions. The antifouling behaviour was also significant as the irreversible fouling (R_Ir 9%), which was found to be minimal for D-BI-incorporated membrane. The blended membranes exhibited good hydrophilicity, antifouling, and fairly good rejection of salts.     

Molecularly imprinted fluorescent polymers as chemosensors for the detection of mercury ions in aqueous media

This article describes the investigation of molecularly imprinted fluorescent polymer membranes as sensing receptors for Hg²⁺ detection by an optical approach. The polymers were synthesized with 4‐vinylpyridine as a functional monomer and Hg²⁺ as a template; 9‐vinylcarbazole was used as both a complex‐forming agent and a fluorescence probe. The free‐radical polymerization was performed within a semicylindrical Teflon mold and was initiated by 2,2′‐azobisisobutyronitrile at 60°C. The template, ion‐bonded to pyridine and carbazole groups in the polymer membrane, was removed by acid treatment. Attenuated total reflectance–Fourier transform infrared (FTIR) spectroscopic measurements and scanning electron microscopy images were used to compare the chemistry and surface morphology, respectively, of both imprinted and nonimprinted polymer materials. The final polymer membranes with semicylindrical shapes were used directly to determine Hg²⁺ concentration in aqueous solutions by the monitoring of the fluorescence intensity of the carbazole groups quenched upon complex formation with metal ions. The values of the Hg²⁺ binding ratio for the imprinted and nonimprinted polymeric membranes were compared, and the results indicate the superior sensitivity and selectivity of the imprinted membranes. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

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.     

Electrochemical oxidation of an acid dye by active chlorine generated using Ti/Sn<Subscript>(1−<Emphasis Type="Italic">x</Emphasis>)</Subscript>Ir<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript>O<Subscript>2</Subscript> electrodes

The generation of active chlorine on Ti/Sn_(1−x)Ir _x O₂ anodes, with different compositions of Ir (x = 0.01, 0.05, 0.10 and 0.30 ), was investigated by controlled current density electrolysis. Using a low concentration of chloride ions (0.05 mol L⁻¹) and a low current density (5 mA cm⁻²) it was possible to produce up to 60 mg L⁻¹ of active chlorine on a Ti/Sn_0.99Ir_0.01O₂ anode. The feasibility of the discoloration of a textile acid azo dye, acid red 29 dye (C.I. 16570), was also investigated with in situ electrogenerated active chlorine on Ti/Sn_(1−x)Ir _x O₂ anodes. The best conditions for 100% discoloration and maximum degradation (70% TOC reduction) were found to be: NaCl pH 4, 25 mA cm⁻² and 6 h of electrolysis. It is suggested that active chlorine generation and/or powerful oxidants such as chlorine radicals and hydroxyl radicals are responsible for promoting faster dye degradation. Rate constants calculated from color decay versus time reveal a zero order reaction at dye concentrations up to 1.0 × 10⁻⁴ mol L⁻¹. Effects of other electrolytes, dye concentration and applied density currents also have been investigated and are discussed.     

Mechanistic Insights on the Formation of High-Valent MnIII/IV=O Species Using Oxygen as Oxidant: A Theoretical Perspective

High-valent metal−oxo species are of great interest as they serve as a robust catalyst for various organic transformations, and at the same time, they offer significant insight into the reactivity of various metalloenzymes. Formation of Mn−Oxo species is of great interest as they are involved in the Oxygen Evolving Complex of Photosystem II, and various bio-mimic models were synthesized to understand its reactivity. In this context, using urea decorated amine ligands, Borovik et al. have reported the facile formation of Mn^III=O and Mn^IV=O species from [Mn^IIH₂buea]²⁻ (here H2buea=tris[(N′-tert-butylureayl)-N-ethyl]amine) precursor complex using oxygen as the oxidant. While reactivity of these species is thoroughly studied, mechanism of formation of such species is scarcely explored. In this work, we have attempted to establish the formation of these species from the Mn^II precursor using the experimental conditions. Our calculations reveal the following fundamental steps in the formation of such species: i) O₂ activation by Mn^II lead to formation of Mn^II−superoxide species wherein the oxidation state of the Mn^II found to be intact upon O₂ binding facilitated by the deprotonated nitrogen atom present in the cavity (ii) in the second step, superoxo species is converted to Mn^II−hydroperoxo species, [Mn^IIH₂buea(OOH)]²⁻ using dimethylacetamide solvent as source for HAT reaction (iii) presence of water molecule found to aid the O−O bond cleavage in [Mn^IIH₂buea(OOH)]²⁻ species leading to the formation of the putative Mn^III=O species, [Mn^IIIH₃buea(O)]²⁻ (iv) one-electron oxidation of Mn^III=O, leads to the formation of [Mn^IVH₃buea(O)]⁻ species and this step is endothermic and need some external oxidants for its formation. While various spin-states and their roles are explored, our calculations reveal that the Mn atom prefers to be in the high-spin state across the potential energy surface studied. However, the nature of the formation is strongly correlated to the spin state arising from the radical nature present in the O₂ moiety and also in the deprotonated nitrogen atom. This offers a unique multistate reactivity channel for the formation these species easing various kinetic barriers across the potential energy surface. Further, we have also computed the spectral parameters for the experimentally observed species, which are in agreement with the reported data offering confidence on the mechanism established. To this end, our study unveils a facile formation of high-valent Mn−Oxo species using O₂ as oxidant and role of water molecules in the formation of such species, and these mechanistic insights are likely to have implications beyond the example studied here.     

Ir/H-ZSM-5 Catalysts in the Selective Reduction of NOx with Hydrocarbons

Three different Ir catalysts supported on H-ZSM-5 were prepared and tested for the selective catalytic reduction of NO under net oxidizing conditions using propene as reducing agent. The preparation of highly active Ir catalysts and the elaboration of a procedure for enhancing activity by on stream conditioning was targeted. Structural changes of the catalyst during conditioning were investigated by means of XRD, TEM and activity measurements. Under reaction conditions Ir was present as Ir⁰ and IrO₂. The presence of Ir⁰ was essential for high DeNOx activity. The ratio of Ir⁰/Ir⁴⁺ was found to depend on the size of Ir-containing crystallites. Larger crystallites contained predominantly Ir⁰. Crystallite size and oxidation state of Ir have been identified to be crucial for the NO reduction behaviour of Ir/H-ZSM-5.     

The DiPPro Approach: Synthesis,Hydrolysis, and Antiviral Activity of Lipophilic d4T Diphosphate Prodrugs

Bioreversible protection of the β‐phosphate group of nucleoside diphosphates (NDPs) as bis(acyloxybenzyl)phosphate esters is presented. To investigate the structure–activity relationship of these potential NDP prodrugs (DiPPro drugs) a series of DiPPro compounds was synthesized bearing fatty acids of various lengths and d4T as a model nucleoside. For synthesis of the lipophilically modified diphosphate group, preformed phosphoramidites were allowed to react with nucleotides, and the β‐P^III moiety was subsequently oxidized. The chemical and enzymatic stability of these prodrugs was studied in different media such as phosphate buffer (pH 7.3) or CEM cell extracts. In all media, the hydrolysis rate was clearly dependent on the acyl moiety and decreased with increasing alkyl chain length. The compounds showed a markedly lower half‐life in cell extracts than in pH 7.3 phosphate buffer due to the presence of enzyme‐catalyzed cleavage. In all media, the DiPPro compounds released d4T diphosphate (d4TDP) as the main product beside d4TMP. In antiviral assays, the compounds proved to be at least as potent as d4T against HIV‐1 and 2 in wild‐type CEM/0 cells. As a proof of concept, compounds with longer acyl residues showed very good anti‐HIV activities in thymidine‐kinase‐deficient cells (CEM/TK^?), indicating their ability to penetrate cell membranes and the delivery of phosphorylated metabolites.     

A Simple DNAzyme-Based Fluorescent Assay for Klebsiella pneumoniae

Pathogenic bacteria pose a serious threat to public health, and the rapid and cost-effective detection of such bacteria remains a major challenge. Herein, we present a DNAzyme-based fluorescent paper sensor for Klebsiella pneumoniae. The DNAzyme was generated by an in vitro selection technique to cleave a fluorogenic DNA–RNA chimeric substrate in the presence of K. pneumoniae. The DNAzyme was printed on a paper substrate in a 96-well format to serve as mix-and-read fluorescent assay that exhibits a limit of detection (LOD) 10⁵ CFUs mL⁻¹. Evaluated with 20 strains of clinical bacterial isolates, the DNAzyme produced the desired fluorescence signal with the samples of K. pneumoniae, regardless of their source or drug resistance. The assay is simple to use, rapid, inexpensive, and avoids the complex procedures of sample preparation and equipment. We believe that this DNAzyme-based fluorescent assay has potential for practical applications to identify K. pneumoniae.     

A Novel Bimetallic Chain Based on [Mo(CN)<Subscript>8</Subscript>]<Superscript>3−</Superscript> and Yb<Superscript>3+</Superscript> Ions as Building Blocks in Which Containing Many Intriguing Structural Features

A novel Mo^V–Yb^III bimetallic chain, {[Yb^III(bpy)₂(DMF)(H₂O)][Mo^V(CN)₈]·0.5bpy·4.5H₂O}_n (1) (DMF = N,N′-dimethylformamide; bpy = 2,2′-bipyridine), has been constructed by the reaction of [Mo(CN)₈]³⁻ with Yb³⁺ and 2,2′-bipyridine. Complex 1 is confirmed as a host–guest supramolecular structure by X-ray structural analysis. The neighboring chains interact with each other with two types of hydrogen bonds and two types of π···π interactions. Thus complex 1 has a unique 3D network. Magnetic analysis of 1 indicates the presence of a strong Yb^III single-ion effect owing to spin–orbital coupling within this system.     

Potential of DMSO as greener solvent for PES ultra‐ and nanofiltration membrane preparation

In this article, the performance of polyethersulfone (PES) ultra‐ and nanofiltration membranes, prepared with the non‐toxic solvent dimethyl sulfoxide (DMSO), was investigated. The membranes were prepared by immersion precipitation via phase inversion. Experimental results proved that DMSO is a better alternative to N‐methyl‐2‐pyrrolidone (NMP) as solvent for PES ultrafiltration membranes as the membranes had a higher permeability and rejection of bovine serum albumin (BSA). An explanation was found based on experimental cloud point data and scanning electron microscopy images showing the morphology. The rejection of BSA and rose Bengal (RB) was proportional to the polymer concentration. On the contrary, the permeability decreased with increasing polymer concentration. For a casting thickness of 250 µm, an optimal balance between permeability and rejection of macromolecules for ultrafiltration was found at 24 wt % PES. The permeability was inversely proportional to the casting thickness, but a small decrease in rejection was observed when lowering the thickness. A good balance between permeability and rejection of RB was found, using a reference nanofiltration membrane of 28.5 wt % PES with 150 µm casting thickness. This membrane achieved a RB rejection of 95.3% and a pure water flux of 2.03 L m^?2 h^?1 bar^?1. The membrane thickness and polymer concentration did not have a clear influence on the hydrophilicity of the membranes. It can be concluded that DMSO is a benign alternative as compared to traditional solvents such as NMP and also results in better PES membrane performances. DMSO is a perfectly suitable solvent for ultrafiltration applications and has potential to be used for nanofiltration applications. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46494.     

FRET-Based In-Cell Detection of Highly Selective Supramolecular Complexes of meso-Tetraarylporphyrin with Peptide/BODIPY-Modified Per-O-Methyl-β-Cyclodextrins

Artificial supramolecular systems capable of self-assembly and that precisely function in biological media are in high demand. Herein, we demonstrate a highly specific host-guest-pair system that functions in living cells. A per-O-methyl-β-cyclodextrin derivative (R8-B-CD^Me) bearing both an octaarginine peptide chain and a BODIPY dye was synthesized as a fluorescent intracellular delivery tool. R8-B-CD^Me was efficiently taken up by HeLa cells through both endocytosis and direct transmembrane pathways. R8-B-CD^Me formed a 2 : 1 inclusion complex with tetrakis(4-sulfonatophenyl)porphyrin (TPPS) as a guest molecule in water, from which fluorescence resonance energy transfer (FRET) from R8-B-CD^Me to TPPS was observed. The FRET phenomenon was clearly detected in living cells using confocal microscopy techniques, which revealed that the formed supramolecular R8-B-CD^Me/TPPS complex was maintained within the cells. The R8-B-CD^Me cytotoxicity assay revealed that the addition of TPPS counteracts the strong cytotoxicity (IC₅₀=16 μM) of the CD cavity due to complexation within the cells. A series of experiments demonstrated the bio-orthogonality of the supramolecular per-O-methyl-β-CD/tetraarylporphyrin host-guest pair in living cells.