Redox-active Metal Complexes Research Articles

Synthesis and Photo/Radiation Chemical Characterization of a New Redox-Stable Pyridine-Triazole Ligand.

Photocatalysis using transition-metal complexes is widely considered the future of effective and affordable clean-air technology. In particular, redox-stable, easily accessible ligands are decisive. Here, we report a straightforward and facile synthesis of a new highly stable 2,6-bis(triazolyl)pyridine ligand, containing a nitrile moiety as a masked anchoring group, using copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction. The reported structure mimics the binding motif of uneasy to synthesize ligands. Pulse radiolysis under oxidizing and reducing conditions provided evidence for the high stability of the formed radical cation and radical anion 2,6-di(1,2,3-triazol-1-yl)-pyridine compound, thus indicating the feasibility of utilizing this as a ligand for redox active metal complexes and the sensitization of metal-oxide semiconductors (e. g., TiO2 nanoparticles or nanotubes).

A solution-processable benzothiazole-substituted formazanate zinc(II) complex designed for a robust resistive memory device.

A novel mononuclear bis(formazanate)zinc complex (1) based on a redox-active 1-(benzothiazol-2-yl)-5-(2-benzoyl-4-chlorophenyl)-3-phenyl formazan ligand has been synthesized and characterized. Complex 1 was prepared by reacting one equivalent of Zn(OCOCH3)·2H2O with two equivalents of the corresponding formazan derivative. X-ray crystallography was employed to ascertain the solid-state structure of compound 1, and the analysis revealed a distorted octahedral geometry for the complex where the symmetrical ligands exhibit a preference for coordinating with the zinc center in the 'open' form, generating five-membered chelate rings. Moreover, cyclic voltammetry analysis reveals that complex 1 exhibits the capacity for electrochemical reduction as well as oxidation, resulting in the formation of radical anionic (L2Zn-) and dianionic (L2Zn2-) states as well as the oxidation state of 1. Additionally, the developed solution-processable complex 1 was employed as the fundamental building material for resistive switching memory applications. The [FTO/ZnIIL2(1)]/Ag RRAM device demonstrates exceptional resistive memory switching properties, with a substantial ION/IOFF ratio (103), low operational VSET and VRESET (0.9 V and -0.75 V) voltages, excellent endurance stability (100 cycles), and decent retention time (more than 2000 seconds). The findings presented in this study underscore the importance of redox-active formazanate metal complexes for creating promising memory storage devices.

Targeting Pathogenic Formate-Dependent Bacteria with a Bioinspired Metallo-Nitroreductase Complex.

Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru-arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant Staphylococcus aureus. This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox-active metal complexes for prodrug activation via bioinspired nitroreduction.

Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy.

Metal-based chemotherapeutics like cisplatin are widely employed in cancer treatment. In the last years, the design of redox-active (transition) metal complexes, such as of copper (Cu), has attracted high interest as alternatives to overcome platinum-induced side-effects. However, several challenges are still faced, including optimal aqueous solubility and efficient intracellular delivery, and strategies like the use of cell-penetrating peptides have been encouraging. In this context, we previously designed a Cu(II) scaffold that exhibited significant reactive oxygen species (ROS)-mediated cytotoxicity. Herein, we build upon the promising Cu(II) redox-active metallic core and aim to potentiate its anticancer activity by rationally tailoring it with solubility- and uptake-enhancing functionalizations that do not alter the ROS-generating Cu(II) center. To this end, sulfonate, arginine and arginine-rich cell-penetrating peptide (CPP) derivatives have been prepared and characterized, and all the resulting complexes preserved the parent Cu(II) coordination core, thereby maintaining its reported redox capabilities. Comparative in vitro assays in several cancer cell lines reveal that while specific solubility-targeting derivatizations (i.e., sulfonate or arginine) did not translate into an improved cytotoxicity, increased intracellular copper delivery via CPP-conjugation promoted an enhanced anticancer activity, already detectable at short treatment times. Additionally, immunofluorescence assays show that the Cu(II) peptide-conjugate distributed throughout the cytosol without lysosomal colocalization, suggesting potential avoidance of endosomal entrapment. Overall, the systematic exploration of the tailored modifications enables us to provide further understanding on structure-activity relationships of redox-active metal-based (Cu(II)) cytotoxic complexes, which contributes to rationalize and improve the design of more efficient redox-mediated metal-based anticancer therapy.

Catalytic and Photocatalytic Functionality of Diprotonated Porphyrins

Development of strategy in energy conversion and storage is indispensable for a sustainable society. So far, redox-active transition metal complexes have been used as efficient catalysts and photosensitizers in energy-converting reactions such as hydrogen evolution through thermal and photoinduced electron transfer (ET).We have been working on development of redox and photochemical functionality of diprotonated saddle-distorted porphyrins based on ET reactions. Herein we would like to highlight recent advance in our study of catalytic dioxygen reduction and hydrogen evolution using diprotonated forms of dodecaphenylporphyrin (H2DPP) derivatives as organocatalysts and photosensitizers.A diprotonated form of a water-soluble H2DPP derivative can act as a photosensitizer (PS) in photocatalytic oxidation of organic substrates in water using Na2S2O8 as an oxidant under visible-light irradiation.1 On the contrary, diprotonated H2DPP has been used as a PS in photocatalytic H2 evolution using platinum nanoparticles as catalysts under near-infrared (710 nm) irradiation in the quantum yield of 17%.2 Diprotonated H2DPP (H4DPP2+) can serve as an organo-photocatalyst in highly selective and efficient O2 reduction to afford H2O2 under photoirradiation at 480 nm; the quantum yield of H2O2 generation was 12% and turnover frequency was 500 h–1.3 Interconversion of O2 and H2O2 has been achieved using an N21,N23-dimethylated H2DPP derivative.4 The porphyrin is reduced by H2O2 to form the corresponding isophlorin derivative as a two-electron-reduced product, which is in turn oxidized by O2 to afford the porphyrin and H2O2. We also developed efficient O2 reduction using N21,N22- and N21,N23-dimethylated H2DPP derivatives as catalysts; in the catalysis, catalytic mechanisms and performance depend on the structures of catalysts used in terms of interaction between O2 and the corresponding isophlorins.5 References T. Ishizuka et al., Green Chem. 2018, 20, 1975.H. Kotani et al., ACS Appl. Energy Mater. 2020, 3, 3193.E. Aoki et al., Chem. Commun. 2019, 55, 4925.W. Suzuki et al., J. Am. Chem. Soc. 2019, 141, 5987.W. Suzuki et al., Chem. Eur. J. 2020, 26, 10480.

Heterospin frustration in a metal-fullerene-bonded semiconductive antiferromagnet

Lithium-ion-encapsulated fullerenes (Li+@C60) are 3D superatoms with rich oxidative states. Here we show a conductive and magnetically frustrated metal–fullerene-bonded framework {[Cu4(Li@C60)(L)(py)4](NTf2)(hexane)}n (1) (L = 1,2,4,5-tetrakis(methanesulfonamido)benzene, py = pyridine, NTf2− = bis(trifluoromethane)sulfonamide anion) prepared from redox-active dinuclear metal complex Cu2(L)(py)4 and lithium-ion-encapsulated fullerene salt (Li+@C60)(NTf2−). Electron donor Cu2(L)(py)2 bonds to acceptor Li+@C60 via eight Cu‒C bonds. Cu–C bond formation stems from spontaneous charge transfer (CT) between Cu2(L)(py)4 and (Li+@C60)(NTf2−) by removing the two-terminal py molecules, yielding triplet ground state [Cu2(L)(py)2]+(Li+@C60•−), evidenced by absorption and electron paramagnetic resonance (EPR) spectra, magnetic properties and quantum chemical calculations. Moreover, Li+@C60•− radicals (S = ½) and Cu2+ ions (S = ½) interact antiferromagnetically in triangular spin lattices in the absence of long-range magnetic ordering to 1.8 K. The low-temperature heat capacity indicated that compound 1 is a potential candidate for an S = ½ quantum spin liquid (QSL).

Bioimaging agents based on redox-active transition metal complexes.

Detecting the fluctuation and distribution of various bioactive species in biological systems is of great importance in determining diseases at their early stages. Metal complex-based probes have attracted considerable attention in bioimaging applications owing to their unique advantages, such as high luminescence, good photostability, large Stokes shifts, low toxicity, and good biocompatibility. In this review, we summarized the development of redox-active transition metal complex-based probes in recent five years with the metal ions of iron, manganese, and copper, which play essential roles in life and can avoid the introduction of exogenous metals into biological systems. The designing principles that afford these complexes with optical or magnetic resonance (MR) imaging properties are elucidated. The applications of the complexes for bioimaging applications of different bioactive species are demonstrated. The current challenges and potential future directions of these probes for applications in biological systems are also discussed.

Second-order NLO properties and two-state switching effects of transition metal redox complexes of iron and cobalt: A DFT study

Designing switchable materials with large contrasts of nonlinear optical properties has been the focus of research in recent decades because of their widespread applications. Redox-active metal complexes due to charge transfer excitation are suitable to produce switchable nonlinear optical (NLO) material. In this regard, we present here the redox switchable NLO response of active metal complexes of iron and cobalt. The geometric, electronic, molecular absorption, nonlinear optical properties, and switch “ON/OFF” style of these metal complexes are studied at the CAM-B3LYP/6-31 + G(d) level of theory. NLO responses of these redox metal complexes are described in terms of change in the charge transfer (CT) patterns by time dependent density functional theory (TD-DFT). The highest βo value of 301534 × 10−30 esu is noticed in [Fe-ethynyl-ZnP]1+ complex, because of obvious charge transfer transition from metal to ligand i.e meatal-ligand charge transfer (MLCT) in redox metal complex. In each redox metal isomeric pair, the greater hyperpolarizability value of individual isomer is quite consistent with its smaller energy gap (H-Lgap) between highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO), low crucial excitation energy, and bathochromic shift of λmax. The remarkable βo contrasts of these isomeric redox complexes illustrate that they can be appropriate for effective redox-triggered NLO switches. Thus, the results reveal that these redox pair complexes show two-state switching “ON/OFF” effect.

Copper(II) Pyridyl Aminophenolates: Hypoxia-Selective, Nucleus-Targeting Cytotoxins, and Magnetic Resonance Probes.

Targeting the low-oxygen (hypoxic) environments found in many tumours by using redox-active metal complexes is a strategy that can enhance efficacy and reduce the side effects of chemotherapies. We have developed a series of CuII complexes with tridentate pyridine aminophenolate-based ligands for preferential activation in the reduction window provided by hypoxic tissues. Furthermore, ligand functionalization with a pendant CF3 group provides a 19 F spectroscopic handle for magnetic-resonance studies of redox processes at the metal centre and behaviour in cellular environments. The phenol group in the ligand backbone was substituted at the para position with H, Cl, and NO2 to modulate the reduction potential of the CuII centre, giving a range of values below the window expected for hypoxic tissues. The NO2 -substituted complex, which has the highest reduction potential, showed enhanced cytotoxic selectivity towards HeLa cells grown under hypoxic conditions. Cell death occurs by apoptosis, as determined by analysis of the cell morphology. A combination of 19 F NMR and ICP-OES indicates localization of the NO2 complex in HeLa cell nuclei and increased cellular accumulation under hypoxia. This correlates with DNA nuclease activity being the likely origin of cytotoxic activity, as demonstrated by cleavage of DNA plasmids in the presence of the CuII nitro complex and a reducing agent. Selective detection of the paramagnetic CuII complexes and their diamagnetic ligands by 19 F MRI suggests hypoxia-targeting theranostic applications by redox activation.

Enhancement of electrocatalytic abilities toward CO2 reduction by tethering redox-active metal complexes to the active site.

Tethering metal complexes, like [Ru(bpy)2Cl2] (bpy = 2,2'-bipyridine), which are redox-active at low reduction potentials and have the ability to transfer electrons to another complex, to a [Ni(cyclen)]2+ electrocatalyst enhanced the reduction of CO2 to CO at low overpotentials. The [Ni(cyclen)]2+ electrocatalyst was modified by tethering redox-active metal complexes via 4-methylpyridyl linkers. The redox-active metal complexes were reduced after CO2 bound to the active site. In controlled potential electrolysis (CPE) experiments in 95 : 5 (v/v) CH3CN/H2O, [{([Ru]pic)4cyclen}NiCl]5+ ([Ru]+ = {Ru(bpy)2Cl}+; pic = 4-methylpyridyl) could be used to reduce CO2 into CO at a turnover frequency (TOF) of 708 s-1 with a faradaic efficiency (FE) of 80% at an onset potential of -1.60 V vs. NHE. At the same time, this electrocatalyst was active at an onset potential of -1.25 V vs. NHE, which is the reduction potential of one of the bpy ligands of the [Ru]+ moieties, with FE = 84% and TOF = 178 s-1. When the electrocatalysis was performed using [bn4cyclenNiCl]Cl (bn = benzyl) without tethered redox-active metal complexes, the TOF value was determined to be 8 s-1 with FE = 77% at an onset potential of -1.45 V vs. NHE. The results show that tethering redox-active metal complexes significantly improves the electrocatalytic activities by lowering the potential needed to reduce CO2.

Catalytic antioxidant nanocomposites based on sequential adsorption of redox active metal complexes and polyelectrolytes on nanoclay particles.

An antioxidant nanocomposite was prepared by successive adsorption of redox active metal complexes (copper(ii)-bipyridyl and iron(iii)-citrate) and polyelectrolytes (poly(styrene sulfonate) and poly(diallyldimethyl ammonium)) on layered double hydroxide nanoclay. The experimental conditions were optimized in each preparation step and thus, the final composite formed highly stable colloids, i.e., excellent resistance against salt-induced aggregation was achieved. Due to the synergistic effect of the metal complexes, the developed composite showed remarkable activity in the dismutation of superoxide radicals, close to the one determined for the native superoxide dismutase enzyme. The obtained composite is highly selective for superoxide radical dismutation, while its activity in other antioxidant tests was close to negligible. Structural characterization of the composite revealed that the excellent superoxide radical scavenging ability originated from the advantageous coordination geometry around the copper(ii) center formed upon immobilization. The structure formed around the metal centers led to optimal redox features and consequently, to an improved superoxide dismutase-like activity. The catalytic antioxidant composite is a promising candidate to reduce oxidative stress in industrial manufacturing processes, where natural enzymes quickly lose their activity due to the harsh environmental conditions.

Synthesis, characterization and biochemical studies of redox active metal complexes with flavone derivative

In the present investigations was focused on the synthesis of flavone derivative (obtained by the condensation of substituted flavone with o-phenylenediammine), dppz with different metal acetates to arrive different mixed ligand metal chelates with molecular formulae of [ML(dppz)]0.2(OAc) where L = flavone derivative; M = Cu(II), Co(II), Ni(II) and Zn(II), respectively. The structural compositions and arrangements were inferred based on elemental compositions, molar conductivity, magnetic properties, electronic absorption, vibrational frequencies, proton assignments, ESR, thermal analysis and cyclic voltammetry protocols. On the basis of spectroscopic approaches established that square planar arrangement for Cu 2+ , Ni 2+ , Co 2+ and Zn 2+ chelates. The DNA cleavage efficiency was performed using agarose gel permeation technique revealed the metal chelates were interacted with DNA induced DNA denaturation. The prepared metal chelates were assessed for antimicrobial efficiency with B.subtilis, E. coli, S.aureus, C. albicans, A.niger and A.flavus . The observed research outcomes were indicated that metal chelates exposed improved antimicrobial efficacies than ligand. Furthermore, SOD biomimetic activity of prepared metal complexes was performed and presented. Antituberculosis competences of ligand and its chelates was assessed against M. tuberculosis H 37 Rv strain with the help of MABA protocol. The prepared metal chelates were subjected to α-glucosidase inhibitory efficiency, anti-inflammatory activity and presented.

Iron chelators in cancer therapy.

Iron chelators have long been a target of interest as anticancer agents. Iron is an important cellular resource involved in cell replication, metabolism and growth. Iron metabolism is modulated in cancer cells reflecting their increased replicative demands. Originally, iron chelators were first developed for use in iron overload disorders, however, their potential as anticancer agents has been gaining increasing interest. This is due, in part, to the downstream effects of iron depletion such as the inhibition of proliferation through ribonucleotide reductase activity. Additionally, some chelators form redox active metal complexes with iron resulting in the production of reactive oxygen species and oxidative stress. Newer synthetic iron chelators such as Deferasirox, Triapine and di-2-pyridylketone-4,4,-dimethyl-3-thiosemicrbazone (Dp44mt) have improved pharmacokinetic properties over the older chelator Deferoxamine. This review examines and discusses the various iron chelators that have been trialled for cancer therapy including both preclinical and clinical studies. The successes and shortcomings of each of the chelators and their use in combination therapies are highlighted and future potential in the cancer therapy world is considered.

Redox-active ferrocene-containing iridium(III) complex for non-volatile flash memory

Abstract A new ferrocene-containing iridium(III) complex (complex 2) has been designed and synthesized. Its structure, photophysical property, electrochemistry and memory behaviors were well investigated. The memory device with a sandwich structure of ITO/complex 2/Al (D2) exhibited flash memory performance with a bistable conductive process, which showed a high ON/OFF current ratio of 103, long retention time of 103 s, and low threshold voltage of −0.55 V. After 105 read cycles, no significant degradation was observed in the ON and OFF states at a read voltage of 1.0 V. The ferrocene group of complex 2 serves as the redox-active unit, and a redox memory mechanism is proposed to explain the conductive process based on the analysis of I–V, cyclic voltammetry and theoretical calculation data. Thus, the design of redox-active metal complex used for novel non-volatile memory device provided an alternative strategy for the further development of organic memory materials and devices.

Recent Advances with Terpyridine-Based Monolayer Electrochromic Materials

Electrochromic (EC) materials are a class of “smart” materials that change their optical properties in response to an applied potential. This optical change can be the development, loss, or variation in the color of the material. EC materials have recently become a research focus because of their high commercial applicability in “smart” windows, antiglare mirrors, and low-power displays. Most current EC materials are based on thick layers of EC molecules or EC molecules/ conductive polymer blends on the electrodes. The device properties depends strongly on the overall composition and distribution of the EC species in the polymer structure. We have developed an EC systems that contain as little as a monolayer of the EC molecules deposited onto a surface-enhanced conductive support [1]. The process involves the covalent attachment of various terpyridine-based ligand to the surface of a nanostructured conductive indium − tin oxide (ITO) screen-printed support by a simple submerging of the support into an aqueous solution of L. Subsequent reaction of with metal ions (e.g. Fe, Ru) leads to the formation the monolayer of the redox-active metal complex covalently bound to the ITO support. In addition, isolated and well-defined terpyridine- based metal complexes (Fe, Os,Co) were simply deposited on ITO screen-printed surface via conventional chlorobenzylsiloxane-based template. Our fabrication approach utilizes the inter-particle porosity of the support and requires as low as a monolayer of EC active molecule, giving significant molecular economy when compared with traditional polymer-based EC devices. This presentation will feature an overview of our synthetic methods, including how we can alter the color of the films by changing either the metal center of the ligand itself [2]. Spectro-electrochemical studies enabled us to correlation optical density with redox site density. Furthermore, detailed electrochemical studies enabled the determination of the kinetic rate constants for electron transfer for these films [3], which were considerably higher than other approaches in the literature. These novel light-reflective EC materials demonstrate a high color difference, significant durability, fast switching speed, excellent stability and high EC reversibility.

Effect of Transition Metal Compounds on the Cyclohexene Oxidation Catalyzed by N-Hydroxyphthalimide

N-Hydroxyphthalimide (NHPI) is an efficient organic catalyst in the oxidation reactions of organic compounds occurring via a radical mechanism, often used together with redox-active ions or transition metal complexes. In this work the catalytic action of NHPI is studied together with Cu(II), Fe(III), and Mo(VI) compounds in the reaction of aerobic oxidation of cyclohexene in an acetonitrile solution at 60°C. It was found that iron(III) benzoate accelerates the reaction by rapidly generating the active form of the phthalimide-N-oxyl radical (PINO) catalyst, but does not cause decomposition of the hydroperoxide. The oxidation product is 2-cyclohexenyl hydroperoxide formed with a selectivity of 85% at a cyclohexene conversion of 50%. Copper(II) acetate initiates oxidation and is capable of catalyzing the radical decomposition of the hydroperoxide and secondary oxidation of allyl oxygenates. When reaching a cyclohexene conversion close to 80%, the overall selectivity to the main products, 2-cyclohexenyl hydroperoxide and 2-cyclohexen-1-on, was 70%. The addition of iron(III) and molybdenum(VI) compounds led to the intensive generation of hydroperoxide and its activation as an electrophilic reactant capable of cyclohexene epoxidation. As a result of the use of the multifunctional three-component NHPI–Mo(VI)–Fe(III) catalyst, cyclohexene oxidation by molecular oxygen occurred with the formation of epoxycyclohexane. The selectivity to the products of cyclohexene epoxidation was close to 50%, which is a value expected from theory.

PO-460 Targeting endoplasmic reticulum stress using thiosemicarbazones to suppress cancer progression

IntroductionEndoplasmic reticulum (ER) stress and its corresponding response, namely, the unfolded protein response (UPR), are activated in cancer cells due to genetic mutations and the hostile microenvironment of tumours. This UPR activation has been demonstrated to be a crucial step in oncogenic transformation and cancer development; even eliciting activity of cancer supporting stromal cells. An innovative strategy is to induce lethal activation of the UPR via the use of novel thiosemicarbazone anti-cancer agents (TCs) developed in my lab. TCs form cellular redox active metal complexes and demonstrate potent and selective anti-tumour and anti-metastatic activity in vivo. Importantly, these agents overcome drug resistance. The most potent of these agents is currently being examined in clinical trials for the treatment of patients with advanced solid tumours in Australia.Material and methodsStudies assessed the mechanisms by which the potent TC, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazones (Dp44mT), alters the UPR in SKNMC neuroepthelioma and PANC1 pancreatic cancer cells using a range of techniques, including western blotting, q-RT-PCR, gene silencing and cell migration assays.Results and discussionsOur studies demonstrate that Dp44mT significantly:1 increased activation of ER stress-associated pro-apoptotic signalling (i.e., p-eIF2α, ATF4 and CHOP);2 increased phosphorylation of IRE1α and XBP1 splicing;3 reduced the expression of molecules involved in ER stress-associated cell survival signalling (e.g., XBP1s and p58IPK);4 activated the transcription factor, ATF6, and its downstream targets (i.e., CHOP and BiP); and5 activated pro-apoptotic p-CaMKII. Moreover, it was demonstrated that anti-oxidants could inhibit TC-mediated activation of the UPR, while pro-oxidants enhanced activity. Moreover, PERK or IRE1α silencing reduced Dp44mT-mediated migration inhibition, demonstrating that PERK or IRE1α can regulate cell migration and the anti-cancer activity of Dp44mT.ConclusionCollectively, these results demonstrate that Dp44mT activates the pro-apoptotic pathways of the UPR, re-sensitising cancer cells to UPR-induced apoptosis while inhibiting cell survival signals. Considering UPR activation in cancers, it is crucial to characterise the effect of cancer therapeutics on the UPR to better predict clinical outcomes and the sub-populations of patients that will benefit from this type of therapy.

OP-25 - Cellular metal sequestration and redox stress by thiosemicarbazones induces endoplasmic reticulum stress in tumors to suppress cancer progression

Endoplasmic reticulum (ER) stress and its response, the UPR, are activated in cancer, inducing oncogenic transformation/progression. An innovative strategy is to induce lethal activation of the UPR using novel thiosemicarbazones (TCs) that form cellular redox active metal complexes. TCs demonstrate potent anti-tumour/-metastatic activity in vivo with a lead agent being assessed in clinical trials in advanced cancer patients (NCT02688101). Hence, studies examined the mechanisms by which TCs alter the UPR in multiple cancer cells to suppress cancer proliferation and migration. Our studies demonstrated that TCs significantly induced high levels of ER stress, increasing the activation of pro-apoptotic UPR signals (i.e., p-eIF2α, ATF4, CHOP), while suppressing UPR survival signals (e.g. XBP1s, p58IPK). In contrast, redox inactive DFO and the ER stress-inducing agent, tunicamycin, had little or no effect on these proteins. Moreover, it was demonstrated that anti-oxidants could inhibit TC-mediated activation of the UPR, while pro-oxidants enhanced activity. Silencing the UPR reduced TC-mediated pro-apoptotic activity and migration inhibition. In conclusion, the induction of lethal ER stress via iron sequestration and the generation of ROS is crucial for the anti-cancer activity of TCs.

Targeting Oncogenic Nuclear Factor Kappa B Signaling with Redox-Active Agents for Cancer Treatment.

Nuclear factor kappa B (NF-κB) signaling is essential under physiologically relevant conditions. However, aberrant activation of this pathway plays a pertinent role in tumorigenesis and contributes to resistance. Recent Advances: The importance of the NF-κB pathway means that its targeting must be specific to avoid side effects. For many currently used therapeutics and those under development, the ability to generate reactive oxygen species (ROS) is a promising strategy. As cancer cells exhibit greater ROS levels than their normal counterparts, they are more sensitive to additional ROS, which may be a potential therapeutic niche. It is known that ROS are involved in (i) the activation of NF-κB signaling, when in sublethal amounts; and (ii) high levels induce cytotoxicity resulting in apoptosis. Indeed, ROS-induced cytotoxicity is valuable for its capabilities in killing cancer cells, but establishing the potency of ROS for effective inhibition of NF-κB signaling is necessary. Indeed, some cancer treatments, currently used, activate NF-κB and may stimulate oncogenesis and confer resistance. Thus, combinatorial approaches using ROS-generating agents alongside conventional therapeutics may prove an effective tactic to reduce NF-κB activity to kill cancer cells. One strategy is the use of thiosemicarbazones, which form redox-active metal complexes that generate high ROS levels to deliver potent antitumor activity. These agents also upregulate the metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), which functions as an NF-κB signaling inhibitor. It is proposed that targeting NF-κB signaling may proffer a new therapeutic niche to improve the efficacy of anticancer regimens.

Enhancement of electrocatalytic abilities for reducing carbon dioxide: functionalization with a redox-active ligand-coordinated metal complex.

A binary system consisting of a ditopic planar pseudo-pincer ligand (qlca = quinoline-2-carbaldehyde (pyridine-2-carbonyl) hydrazone) coordinated to two metal centres affording [{Ru(bpy)2}(μ-qlca)NiCl2]Cl·4H2O·CH3OH (2) (bpy = 2,2'-bipyridine) is reported. The Ni2+ moiety acts as the electrocatalytic active site for CO2 reduction to CO. The turnover frequency (TOF) increased from 0.83 s-1 for [Ni(qlca)Cl2] (3) to 120 s-1 for 2, and the overpotential is 350 mV less than that for 3 due to the electronic influence of the {Ru(bpy)2}2+ moiety on the catalytic active site.