A new biphenol-dipicolylamine based ligand and its dinuclear Zn2+ complex as fluorescent sensors for ibuprofen and ketoprofen in aqueous solution.

In this work, the study of the new ligand 3,3'-bis[N,N-bis(pyridine-2-ylmethyl)aminomethyl]-2,2'-dihydroxybiphenyl (L) is reported, where a central 2,2'-biphenol (BPH) fluorophore was functionalized at 3,3'-positions with two dipicolylamine (DPA) side arms as receptor units. Following the synthesis and full chemical-physical characterization, the acid-base and Zn2+-coordination abilities of L were investigated through a combination of potentiometric, UV-Vis, fluorescence, NMR, XRD and DFT measurements. The optical properties of the ligand turned out to be strongly dependent on the pH, being straightforwardly associated with the protonation state of the BPH moiety, whereas its peculiar design allowed to form stable mono and dinuclear Zn2+ complexes. In the latter species, the presence of two Zn2+ ions coordinatively unsaturated and placed at close distance to each other, prompted us to test their usefulness as metallo-receptors for two environmental pollutants of great relevance, ibuprofen and ketoprofen. Potentiometric and fluorescence investigations evidenced that these important non-steroidal anti-inflammatory drugs (NSAIDs) are effectively coordinated by the metallo-receptors and, of relevance, both the stability and the fluorescence properties of the resulting ternary adducts are markedly affected by the different chemical architectures of the two substrates. This study aims at highlighting the promising perspectives arising from the use of polyamino phenolic ligands as chemosensors for H+/Zn2+ and other additional anionic targets in their metal-complexed forms.

Ruthenium(II) polypyridyl complexes with benzoxazole derivatives and non-innocent ligands as effective antioxidants in human neuroblasts.

Ruthenium(II) polypyridyl complexes continue to raise increasing interest for the encouraging results in several biomedical areas. Considering their vast chemical-physical repertoire, in particular the possibility to switch from the sensitization of reactive oxygen species (ROS) to ROS-scavenging abilities by tuning the nature of their ligands, it is therefore surprising that their potential as antioxidants has not been largely investigated so far. Herein, we explored the antioxidant behaviour of the novel ruthenium compound [Ru(dbpy)(2,3-DAN)Cl]PF6 (Ru1), featuring a benzoxazole derivative (dpby = 2,6-bis(4-methyl-2-ossazolyl)pyridine) and the non-innocent 2,3-diamminonaftalene (2,3 DAN) ligand, along with the reference tpy-containing analogue [Ru(tpy)(2,3-DAN)Cl]PF6 (Ru2) (tpy = 2,2':6',2''-terpyridine). Following the synthesis and the electrochemical characterization, chemical antioxidant assays highlighted the beneficial role of dpby for the ROS-scavenging properties of Ru1. These data have been corroborated by the highest protective effect of Ru1 against the oxidative stress induced in SH-SY5Y human neuroblastoma, which exerts pro-survival and anti-inflammatory actions. The results herein reported highlight the potential of Ru1 as pharmacological tool in neurodegenerative diseases and specially prove that the antioxidant properties of such compounds are likely the result of a non-trivial synergetic action involving the bioactive ligands in their chemical architectures.

Flow cytometric analysis of hepatopancreatic cells from Armadillidium vulgare highlights terrestrial isopods as efficient environmental bioindicators in ex vivo settings.

Several studies have reported the high bioindication capacity of Isopoda (Crustacea, Oniscidea), which is related to their important ability to accumulate contaminants, usefulness in soil ecotoxicology and bioindication activities. Any change in the isopod population, diversity and life cycle can indicate relevant pollution levels. The analysis of target tissues, such as the hepatopancreas, is another emerging approach (from a cytologic/histological level) to detect contaminant accumulation from different sources. In this study, tissue disaggregation procedures were optimised in the hepatopancreas, and flow cytometry (FC) was applied to detect cell viability and several cell functions. After disaggregation, two hepatopancreatic cell types, small (S) and big (B), were still recognisable: they differed in morphology and behaviour. The analyses were conducted for the first time on isopods from sites under different conditions of ecological disturbance through cytometric re-interpretation of ecological-environmental parameters. Significant differences in cell functional parameters were found, highlighting that isopod hepatopancreatic cells can be efficiently analysed by FC and represent standardisable, early biological indicators, tracing environmental-induced stress through cytologic/histologic analyses.

Polyethylene pipes exposed to chlorine dioxide in drinking water supply system: A critical review of degradation mechanisms and accelerated aging methods.

Polyethylene (PE) pipes have been widely used in drinking water distribution systems across the world. In many cases, chlorine dioxide (ClO2) is used to maintain a residual disinfectant concentration in potable water. Practical experiences have shown that the lifetime of PE pipes is significantly reduced due to exposure to drinking water with ClO2. Recently, many companies have proposed new PE pipes with a modified formulation, which are more resistant to chlorine dioxide. However, a standardized test method for evaluating the long-term performances of PE pipes is still missing. This literature review was performed to provide a description of chlorine dioxide uses and degradation mechanisms of polyethylene pipes in real water distribution systems. Current accelerated aging methods to evaluate long-term performances of PE pipes exposed to ClO2 are described and discussed along with the common technics used to characterize the specimens. Accelerate aging methods can be distinguished in immersion aging tests and pressurized pipe loop tests. Wide ranges of operational conditions (chlorine dioxide concentration, water pressure, water temperature, etc.) are applied, resulting in a great variety of results. It was concluded that pressurized looping tests applying semi-realistic operational conditions could better replicate the aging mechanisms occurring in service. Despite this, the acceleration and the evaluation of the long-term performance are still difficult to determine precisely. Further experimentation is needed to correlate chemical-mechanical characterization parameters of PE pipes with their lifetime in service.

A novel 2,6-bis(benzoxazolyl)phenol macrocyclic chemosensor with enhanced fluorophore properties by photoinduced intramolecular proton transfer.

Macrocyclic ligand L, in which a 2,6-bis(2-benzoxazolyl)phenol (bis-HBO) group is incorporated in triethylenetetramine, was designed and synthesized with the aim of creating a chemosensor with high selectivity and specificity for metal cations in an aqueous environment. The availability of several proton acceptors and donors, and amine and phenol hydroxy groups, respectively, affects the keto-enol equilibrium in both the ground and excited states, and the ligand properties show dependence on the pH of the solution. L is fluorescent in the visible range, through an excited-state intramolecular proton transfer (ESIPT) mechanism. The results of an exhaustive characterization of L by spectroscopic techniques and DFT calculations, as well as of its Zn(II), Cd(II) and Pb(II) complexes, show promising properties of L as a ratiometric metal cation chemosensor, since metal coordination prevents the ESIPT and gives rise to a peculiar displacement of the fluorescence emission from green to blue with Zn(II) and Cd(II), while with Pb(II) the fluorescence is quenched.

Fluorescent sensing of non-steroidal anti-inflammatory drugs naproxen and ketoprofen by dansylated squaramide-based receptors.

Bis-squaramide receptors L1-L4 bearing a dansyl moiety were synthesised and their potential applications as fluorescent probes towards non steroidal anti-inflammatory drugs naproxen and ketoprofen was investigated. A detailed photophysical characterization in CH3CN/DMSO solution (9 : 1 v/v) was conducted and demonstrated that the two macrocyclic receptors L1 and L2 show good sensitivity towards ketoprofen with an ON-OFF fluorescent response, while the two open chain receptors L3 and L4 behave similarly with the three guests considered. DFT theoretical calculations carried out on L2 and L4 as model receptors allowed to propose a possible coordination mode towards the guests. Finally, 1H-NMR spectroscopy in DMSO-d6/0.5% water solution demonstrated that the four receptors interact with the considered guests via H-bonds.

A New Family of Macrocyclic Polyamino Biphenolic Ligands: Acid-Base Study, Zn(II) Coordination and Glyphosate/AMPA Binding.

In this study, the ligands 23,24-dihydroxy-3,6,9,12-tetraazatricyclo[17.3.1.1(14,18)]eicosatetra-1(23),14,16,18(24),19,21-hexaene, L1, and 26,27-dihidroxy-3,6,9,12,15-pentaazatricyclo[20.3.1.1(17,21)]eicosaepta-1(26),17,19,21(27),22,24-hexaene, L2, were synthesized: they represent a new class of molecules containing a biphenol unit inserted into a macrocyclic polyamine fragment. The previously synthesized L2 is obtained herein with a more advantageous procedure. The acid-base and Zn(II)-binding properties of L1 and L2 were investigated through potentiometric, UV-Vis, and fluorescence studies, revealing their possible use as chemosensors of H+ and Zn(II). The new peculiar design of L1 and L2 afforded the formation in an aqueous solution of stable Zn(II) mono (LogK 12.14 and 12.98 for L1 and L2, respectively) and dinuclear (LogK 10.16 for L2) complexes, which can be in turn exploited as metallo-receptors for the binding of external guests, such as the popular herbicide glyphosate (N-(phosphonomethyl)glycine, PMG) and its primary metabolite, the aminomethylphosphonic acid (AMPA). Potentiometric studies revealed that PMG forms more stable complexes than AMPA with both L1- and L2-Zn(II) complexes, moreover PMG showed higher affinity for L2 than for L1. Fluorescence studies showed instead that the L1-Zn(II) complex could signal the presence of AMPA through a partial quenching of the fluorescence emission. These studies unveiled therefore the utility of polyamino-phenolic ligands in the design of promising metallo-receptors for elusive environmental targets.

A Tetranuclear Copper(II)/Calcium(II) Complex as Dual Chemosensor for Colorimetric and Fluorescent Detection of Non-Steroidal Anti-Inflammatory Drugs.

The tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ complex based on Malten ligand has been investigated as a platform for anion binding. Simple organic carboxylates and non-steroidal anti-inflammatory drugs (NSAIDs) have been tested, revealing the ability of the platform to bind them. The receiving platform hosts at least two guests in solution although a third anion can be bound, as suggested by X-ray diffraction analysis. The addition of the anions is accompanied by a color change of the solution, making the system a colorimetric sensor for carboxylates (LOD values comprised between 3.6 and 20.7 ppm). A fluorescent system consisting of the 2-(3-oxido-6-oxoxanthen-9-yl)benzoate (fluorescein anion) linked to the tetranuclear platform has been also prepared and used in a chemosensing ensemble approach to signal the presence of the selected anions (Log K between 2.6 and 5.6 for the addition of two guests). The latter also works in a paper strip test, offering the chemosensor a possible practical application.

Small molecule-induced epigenomic reprogramming of APL blasts leading to antiviral-like response and c-MYC downregulation.

Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML) in which the PML/RARα fusion protein exerts oncogenic activities by recruiting repressive complexes to the promoter of specific target genes. Other epigenetic perturbations, as alterations of histone H3 lysine 9 trimethylation (H3K9me3), have been frequently found in AMLs and are associated with leukemogenesis and leukemia progression. Here, we characterized the epigenomic effects of maltonis, a novel maltol-derived molecule, in APL cells. We demonstrate that maltonis treatments induce a profound remodulation of the histone code, reducing global H3K9me3 signal and modulating other histone post-translational modifications. Transcriptomic and epigenomic analyses revealed that maltonis exposure induces changes of genes expression associated with a genomic redistribution of histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 acetylation (H3K27ac). Upregulation of interferon alpha and gamma response and downregulation of c-MYC target genes, in function of c-MYC reduced expression (monitored in all the hematopoietic neoplasms tested), represent the most significant modulated pathways. These data demonstrate the ability of maltonis to epigenetically reprogram the gene expression profile of APL cells, inducing an intriguing antiviral-like response, concomitantly with the downregulation of c-MYC-related pathways, thus making it an attractive candidate for antileukemic therapy.

Selective Detection of Mg2+ for Sensing Applications in Drinking Water.

A new series of ligands containing the 2-(2-hydroxy-3- naphthyl)-4-methylbenzoxazole (HNBO) fluorophore showed selectivity for Mg2+ ions, without the interference of Ca2+ . The most promising representative L3 resulted the best performing sensor for Mg2+ both in solution and embedded in an all-solid-state optode, especially towards real samples of drinkable water.

Characterization of a fluorescent 1,8-naphthalimide-functionalized PAMAM dendrimer and its Cu(ii) complexes as cytotoxic drugs: EPR and biological studies in myeloid tumor cells.

The activity and interacting ability of a polyamidoamine (PAMAM) dendrimer modified with 4-N-methylpiperazine-1,8-naphthalimide units (termed D) and complexed by Cu(ii) ions, towards healthy and cancer cells were studied. Comparative electron paramagnetic resonance (EPR) studies of the Cu(ii)-D complex are presented: coordination mode, chemical structure, flexibility and stability of these complexes, in the absence and presence of myeloid cancer cells and peripheral blood mononuclear cells (PBMC). The interactions of Cu(ii) ions in the biological media at different equilibrium times were studied, highlighting different stability and interacting conditions with the cells. Furthermore, flow cytometry and confocal analysis, trace the peculiar properties of the dendrimers in PBMC and U937 cells. Indeed, a new probe (Fly) was used as a potential fluorescent tool for biological imaging of Cu(ii). The study highlights that dendrimer and, mainly, the Cu(ii) metallodendrimer are cytotoxic agents for the cells, specifically for U937 tumor cells, inducing mitochondrial dysfunction, ROS increase and lysosome involvement. The metallodendrimer shows antitumor selectivity, fewer affecting healthy PBMC, inducing a massive apoptotic cell death on U937 cells, in line with the high stability of this complex, as verified by EPR studies. The results underline the potentiality of this metallodendrimer to be used as anticancer drug.

A selective fluorescent probe for gadoliniumIII in water based on a PdII-preorganized chromone-receptor.

The synthesis, solution studies, photochemical properties and the X-ray structure of a chromone based fluorescent PdII complex are reported. The ligand contains two chromone units linked as side arms to an ethylenediamine moiety; in the PdII complex the metal ion preorganizes the two hydroxychromone units forming a rigid structure with a negatively charged pocket formed by four oxygen atoms that is able to interact with hard metal cations, such as ions, giving rise to stable bimetallic complexes. Upon interaction with LaIII and GdIII, in particular, the emission intensity at 423 nm increases by a factor of 2 and 8, respectively, while the other rare earth ions quench the fluorescence. Spectrofluorimetric studies on real matrices showed the possibility to use this system as a selective fluorescence probe to detect and trace the presence of Gadolinium in environmental water acting as an OFF-ON chemosensor, with a LOD of 0.4 ppm and a LOQ of 1.2 ppm.

Synthesis and biological characterization of a new fluorescent probe for vesicular trafficking based on polyazamacrocycle derivative.

The fluorescent probes represent an important tool in the biological study, in fact characterization of cellular structures and organelles are an important tool-target for understanding the mechanisms regulating most biological processes. Recently, a series of polyamino-macrocycles based on 1,4,7,10-tetraazacyclododecane was synthesized, bearing one or two NBD units (AJ2NBD·4HCl) useful as sensors for metal cations and halides able to target and to detect apolar environment, as lipid membranes. In this paper, we firstly illustrate the chemical synthesis of the AJ2NBD probe, its electronic absorption spectra and its behavior regarding pH of the environment. Lack of any cellular toxicity and an efficient labelling on fresh, living cells was demonstrated, allowing the use of AJ2NBD in biological studies. In particular, this green fluorescent probe may represent a potential dye for the compartments involved in the endosomal/autophagic pathway. This research's field should benefit from the use of AJ2NBD as a vesicular tracer, however, to ensure the precise nature of vesicles/vacuoles traced by this new probe, other more specific tests are needed.

A Metal-Based Receptor for Selective Coordination and Fluorescent Sensing of Chloride.

A scorpionate Zn2+ complex, constituted by a macrocyclic pyridinophane core attached to a pendant arm containing a fluorescent pyridyl-oxadiazole-phenyl unit (PyPD), has been shown to selectively recognize chloride anions, giving rise to changes in fluorescence emission that are clearly visible under a 365 nm UV lamp. This recognition event has been studied by means of absorption, fluorescence, and NMR spectroscopy, and it involves the intramolecular displacement of the PyPD unit by chloride anions. Moreover, since the chromophore is not removed from the system after the recognition event, the fluorescence can readily be restored by elimination of the bound chloride anion.

Hetero-Tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ Architectures Based On Malten Ligand: Scaffold for Anion Binding.

The hetero-tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ complex obtained with the N,N'-bis((3-hydroxy-4-pyron-2-yl)methyl)-N,N'-dimethylethylendiamine (Malten) ligand has been studied in solid and solution states as scaffold to bind anions. Three crystal structures showing the same metal ions sequence have been examined; they display a tetracharged complex cation neutralized by four monocharged anions. The anions play two different roles: as coordinated (two ClO4- , Cl- or NO3- ) or ancillary (two ClO4- ) guests. The tetranuclear scaffold hosts two anions also in aqueous and ethanol solutions. Spectrophotometric studies in ethanol allowed to determine the addition constant values for Cl- and Br- (Log K1-2 =4.43(4), 4.39(3) for Cl- , 3.80(3), 3.54(2) for Br- ) while the others, although bound, showed lower affinity for the scaffold. Both the crystals and the solutions change their color depending on the added anion, namely pink, dark green or blue in the presence of ClO4- , Cl- or NO3- , respectively, thus the presence of the different anions is visible to the naked eye. The hetero-tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ complex is a versatile architecture to be used as scaffold for anion binding.

Zn(ii) detection and biological activity of a macrocycle containing a bis(oxadiazole)pyridine derivative as fluorophore.

The synthesis, photochemical properties, biological effects and the X-ray crystal structure of a fluorescent polyamine macrocycle L are reported. L is a polyamine cyclophane macrocycle in which 2,6-bis(5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl)pyridine (POXAPy) acts as a fluorescent sensor and the polyamine as a metal ion binding unit. L performs as a PET-mediated chemosensor, with a maximum emission wavelength close to 360 nm. This gives rise to a signal that is visible to the naked eye in the blue visible range. L is able to detect the Zn(ii) and Cd(ii) metal ions in an aqueous solution at pH = 7, with the coordination of the ions switching the emission ON through a CHEF effect. In contrast, paramagnetic metal ions like Cu(ii) and Ni(ii) completely quench the already low emission of L at this pH value. L affects the cell survival of a leukemic cellular model (U937) at micromolar concentrations with cell death starting after only 24 h of exposure; starting from a final concentration of 5 µM, L almost completely abrogates the survival of the leukemic cells over 72 h, with a mechanism that is compatible with a genomic DNA interaction.

Playing with Structural Parameters: Synthesis and Characterization of Two New Maltol-Based Ligands with Binding and Antineoplastic Properties.

Two maltol-based ligands, N,N'-bis((3-hydroxy-4-pyron-2-yl)methyl)-1,4-piperazine (L1) and N,N',N'-tris((3-hydroxy-4-pyron-2-yl)methyl)-N-methylethylendiamine (L2), were synthesized and characterized. L1 and L2, containing, respectively, two and three maltol units spaced by a diamine fragment, were designed to evaluate how biological and binding features are affected by structural modifications of the parent compound malten. The acid-base behavior and the binding properties towards transition, alkaline-earth (AE) and rare-earth (RE) cations in aqueous solution, studied by potentiometric, UV-Vis and NMR analysis, are reported along with biological studies on DNA and leukemia cells. Both ligands form stable complexes with Cu(II), Zn(II) and Co(II) that were studied as metallo-receptors for AE and RE at neutral pH. L1 complexes are more affected than L2 ones by hard cations, the L1-Cu(II) system being deeply affected by RE. The structural modifications altered the mechanism of action: L1 partially maintains the ability to induce structural alterations of DNA, while L2 provokes single strand (nicks) and to a lesser extent double strand breaks of DNA.

Zn2+ and Cu2+ complexes of a fluorescent scorpiand-type oxadiazole azamacrocyclic ligand: crystal structures, solution studies and optical properties.

A ligand comprised of a macrocyclic pyridinophane core having a pendant arm containing a secondary amine group linked through a methylene spacer to a pyridyl-oxadiazole-phenyl (PyPD) fluorescent system has been prepared (L). The crystal structures of [ZnL](ClO4)2 and [CuL](ClO4)2 show that M2+ is coordinated to all the nitrogen atoms of the macrocyclic core, the secondary amine of the pendant arm and the nitrogen atom of the pyridine group of the fluorescent moiety, the latter bond being clearly weaker than the one with the pyridine of the macrocycle. Solution studies showed the formation of a highly stable Cu2+ complex with 1 : 1 stoichiometry, whereas with Zn2+ least stable complexes were formed and, given the right conditions, a [Zn3L2]6+ species was also detected, but it was not possible to isolate this species in the solid state. Following Zn2+ coordination, a strong chelation-induced enhancement of fluorescence was observed, a behaviour that was not observed with any of the other metal cations tested.

A Fluorescent Sensor Array Based on Heteroatomic Macrocyclic Fluorophores for the Detection of Polluting Species in Natural Water Samples.

The development of a novel all-solid-state optical sensor array based on heteroatomic macrocyclic fluorophores (diaza-crown ether, metallocorrole and pyridinophans) for the photographic analysis of liquid media, is presented. The sensitivity of the new optical system toward a number of different species (cations: Li+, K+, Na+, NH4+ , Mg2+, Ca2+, Co2+, Cu2+, Zn2+, Cd2+, Pb2+ and anions: NO2- , NO3- , Cl-, Br-, HCO3- ) was evaluated both in single selective sensor mode and in multisensory arrangement. The satisfactory PLS1 regression models between sensor array optical response and analyte concentration were obtained for Cd2+, Cu2+, Zn2+, and NO2- ions in all the range of tested concentrations. Among these species the highest attention was focused onto detection of cadmium and nitrite ions, for which the detection limits, DL, estimated by 3σ method were found 0.0013 mg/L and 0.21 mg/L respectively, and these values are lower than the corresponding WHO guideline values of 0.003 mg/L (Cd2+) and 2 mg/L ( NO2- ). The suitability of the developed sensors implemented with familiar devices for signal acquisition (Light Emitting Diode, LED, as light source and a digital camera as a signal detector), and chemometric methods for data treatment to perform fast and low-cost monitoring of species under interest, in real samples of environmental importance, is demonstrated.

Crystal structure of the BaII-based CoII-containing one-dimensional coordination polymer poly[[aqua{µ4-2,2'-[(4,10-dimethyl-1,4,7,10-tetra-aza-cyclo-dodecane-1,7-di-yl)bis(methylidene)]bis-(4-oxo-4H-pyran-3-olato)}-perchloratocobaltbarium] perchlorate].

The title compound, {[Ba{Co(H-2L1)}(ClO4)(H2O)]ClO4} n , L1 = 4,10-bis-[(3-hy-droxy-4-pyron-2-yl)meth-yl]-1,7-dimethyl-1,4,7,10-tetra-aza-cyclo-dodeca-ne, is a one-dimensional coordination polymer. The asymmetric unit consists of a {Ba[Co(H-2L1)](ClO4)(H2O)}+ cationic fragment and a non-coordinating ClO4- anion. In the neutral [Co(H-2L1)] moiety, the cobalt ion is hexa-coordinated in a trigonal-prismatic fashion by the surrounding N4O2 donor set. The Ba2+ ion is nine-coordinated and exhibits a distorted [BaO9] monocapped square-anti-prismatic geometry, the six oxygen atoms coming from three distinct [Co(H-2L1)] moieties, while the remaining three vertices are occupied by the oxygen atoms of a bidentate perchlorate anion and a water mol-ecule. A barium-µ2-oxygen motif develops along the a axis, connecting symmetry-related dinuclear BaII-CoII cationic fragments in a wave-like chain, forming a one-dimensional metal coordination polymer. Non-coordinating ClO4- anions are located in the space between the chains. Weak C-H⋯O hydrogen bonds involving both coordinating and non-coordinating perchlorate anions build the whole crystal architecture. To our knowledge, this is the first example of a macrocyclic ligand forming a BaII-based one-dimensional coordination polymer, containing CoII ions surrounded by a N4O2 donor set.