Pyrene-Containing Polyamines as Fluorescent Receptors for Recognition of PFOA in Aqueous Media.

The globally widespread perfluorooctanoic acid (PFOA) is a concerning environmental contaminant, with a possible toxic long-term effects on the environment and human health The development of sensible, rapid, and low-cost detection systems is a current change in modern environmental chemistry. In this context, two triamine-based chemosensors, L1 and L2, containing a fluorescent pyrene unit, and their Zn(II) complexes are proposed as fluorescent probes for the detection of PFOA in aqueous media. Binding studies carried out by means of fluorescence and NMR titrations highlight that protonated forms of the receptors can interact with the carboxylate group of PFOA, thanks to salt bridge formation with the ammonium groups of the aliphatic chain. This interaction induces a decrease in the fluorescence emission of pyrene at neutral and slightly acidic pH values. Similarly, emission quenching has also been observed upon coordination of PFOA by the Zn(II) complexes of the receptors. These results evidence that simple polyamine-based molecular receptors can be employed for the optical recognition of harmful pollutant molecules, such as PFOA, in aqueous media.

Evaluation of coumarin-tagged deferoxamine as a Zr(IV)-based PET/fluorescence dual imaging probe.

Desferoxamine (DFO) is currently the golden standard chelator for 89Zr4+, a promising nuclide for positron emission tomography imaging (PET). The natural siderophore DFO had previously been conjugated with fluorophores to obtain Fe(III) sensing molecules. In this study, a fluorescent coumarin derivative of DFO (DFOC) has been prepared and characterized (potentiometry, UV-Vis spectroscopy) for what concerns its protonation and metal coordination properties towards PET-relevant ions (Cu(II), Zr(IV)), evidencing strong similarity with pristine DFO. Retention of DFOC fluorescence emission upon metal binding has been checked (fluorescence spectrophotometry), as it would - and does - allow for optical (fluorescent) imaging, thus unlocking bimodal (PET/fluorescence) imaging for 89Zr(IV) tracers. Crystal violet and MTT assays on NIH-3 T3 fibroblasts and MDA-MB 231 mammary adenocarcinoma cell lines demonstrated, respectively, no cytotoxicity nor metabolic impairment at usual radiodiagnostic concentrations of ZrDFOC. Clonogenic colony-forming assay performed on X-irradiated MDA-MB 231 cells showed no interference of ZrDFOC with radiosensitivity. Morphological biodistribution (confocal fluorescence, transmission electron microscopy) assays on the same cells suggested internalization of the complex through endocytosis. Overall, these results support fluorophore-tagged DFO as a suitable option to achieve dual imaging (PET/fluorescence) probes based on 89Zr.

Inorganic anion recognition in aqueous solution by coupling nearby highly hydrophilic and hydrophobic moieties in a macrocyclic receptor.

Receptor L, composed of a tripropylenetetramine chain linking the 2 and 7 positions of an acridine unit via methylene bridges, behaves as a pentaprotic base in aqueous solution. The first four protonation steps occur on the tetra-amine chain, while the acridine nitrogen protonates only below pH 4. The penta-protonated receptor assumes a folded conformation, resulting in a cleft delimited by the aliphatic tetramine and acridine moieties, in which anions of appropriate size can be hosted. Potentiometric titrations reveal that F- forms the most stable complexes, although the stability constants of the Cl- and Br- adducts are unusually only slightly lower than those observed for F- complexes. A remarkable drop in stability is observed in the case of I- adducts. Oxo-anions, including H2PO4-, NO3- and SO42-, are not bound or weakly bound by the protonated receptor, despite the known ability of charged oxygens to form stable O-⋯HN+ salt bridges. This unexpected stability pattern is explained in the light of the X-ray crystal structures of H5LCl5·4H2O, H5LBr5·4H2O, H5L(NO3)5·3H2O and H5L(H2PO4)5·(H3PO4)2·4H2O complexes, coupled with MD simulations performed in the presence of explicit water molecules, which reveal that Cl- and, overall, Br- possess the optimal size to fit the receptor cleft, simultaneously forming strong salt bridging interactions with the ammonium groups and anion⋯π contacts with protonated acridine. I- and oxo-anions are too large to conveniently fit the cavity and are only partially enclosed in the receptor pocket, remaining exposed to solvent, with a lower entropic stabilization of their complexes. Although F- could be enclosed in the cavity, its smaller size favours the F-⋯HN+ salt bridging interaction from outside the receptor pocket. The fluorescence emission of the acridinium unit is quenched by anion binding. The quenching ability parallels the stability of the complexes and is related to the relevance of the anion⋯π contacts in the overall host-guest interaction.

Polyamine receptors containing anthracene as fluorescent probes for ketoprofen in H2O/EtOH solution.

Triamine receptors containing anthracene units are able to bind and sense ketoprofen via fluorescence enhancement in a H2O/EtOH 50 : 50 (Vol : Vol) mixture exploiting their protonation features, which are tuned by the interaction with the analyte.

Glyphosate sensing in aqueous solutions by fluorescent zinc(II) complexes of [9]aneN3-based receptors.

Herein we describe the binding abilities of Zn(II) complexes of [12]aneN4- (L1) and [9]aneN3-based receptors (L2, L3) towards the herbicides N-(phosphonomethyl)glycine (glyphosate, H3PMG) and 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid (glufosinate, H2GLU), and also aminomethylphosphonic acid (H2AMPA), the main metabolite of H3PMG, and phosphate. All ligands form stable Zn(II) complexes, whose coordination geometries allow a possible interaction of the metal center with exogenous anionic substrates. Potentiometric studies evidenced the marked coordination ability of the L2/Zn(II) system for the analytes considered, with a preferential binding affinity for H3PMG over the other substrates, in a wide range of pH values. 1H and 31P NMR experiments supported the effective coordination of such substrates by the Zn(II) complex of L2, while fluorescence titrations and a test strip experiment were performed to evaluate whether the H3PMG recognition processes could be detected by fluorescence signaling.

Exploring the Ability of Luminescent Metal Assemblies to Bind and Sense Anionic or Ionizable Analytes A Ru(phen)2bipy-Based Dizinc Complex for Bisphenol A (BPA) Recognition.

The synthesis of a new RuII complex, in which the metal is coordinated by two 1,10-phenanthroline ligands and a 2,2'-bipyridyl unit linked, via methylene bridges in its 4 and 4' positions, to two 1,4,7,10-tetraazacyclododecane (cyclen) macrocycles ([Ru(phen)2 L]2+) is reported. Protonation and ZnII binding by [Ru(phen)2 L]2+ have been analyzed by potentiometric titration, evidencing the formation of mixed hetero-binuclear and hetero-trinuclear ZnII/RuII complexes. These complexes were tested as bis-phenol A (BPA) binders. Only the dizinc complex with [Ru(phen)2 L]2+ is able to bind BPA in aqueous solution, affording a remarkably stable {Zn2[Ru(phen)2 L]BPA(H-2)}4+ adduct at neutral pH, in which BPA is bound in its doubly deprotonated form to the two ZnII ions. BPA binding was found to quench the luminescence emission of the RuII(phen)2bipy core. Although the quenching effect is modest, this study demonstrates that appropriately designed dizinc complexes can be used for binding and optical sensing of BPA in water.

Probing Vibrational Symmetry Effects and Nuclear Spin Economy Principles in Molecular Spin Qubits.

The selection of molecular spin qubits with a long coherence time, Tm, is a central task for implementing molecule-based quantum technologies. Even if a sufficiently long Tm can be achieved through an efficient synthetic strategy and ad hoc experimental measurement procedures, many factors contributing to the loss of coherence still need to be thoroughly investigated and understood. Vibrational properties and nuclear spins of hydrogens are two of them. The former plays a paramount role, but a detailed theoretical investigation aimed at studying their effects on the spin dynamics of molecular complexes such as the benchmark phthalocyanine (Pc) is still missing, whereas the effect of the latter deserves to be examined in detail for such a class of compounds. In this work, we adopted a combined theoretical and experimental approach to investigate the relaxation properties of classical [Cu(Pc)] and a CuII complex based on the ligand tetrakis(thiadiazole)porphyrazine (H2TTDPz), characterized by a hydrogen-free molecular structure. Systematic calculations of molecular vibrations exemplify the effect of normal modes on the spin-lattice relaxation process, unveiling a different contribution to T1 depending on the symmetry of normal modes. Moreover, we observed that an appreciable Tm enhancement could be achieved by removing hydrogens from the ligand.

Aza- and Mixed Thia/Aza-Macrocyclic Receptors with Quinoline-Bearing Pendant Arms for Optical Discrimination of Zinc(II) or Cadmium(II) Ions.

The synthesis and coordination properties of two fluorescent chemosensors, featuring [9]aneN3 (1,4,7-triazacyclononane; L1) and [12]aneNS3 (1-aza-4,7,10-trithiacyclododecane; L2) as receptor units, and a quinoline pendant arm with an amide group as a functional group spacer are described. The optical responses of L1 and L2 in the presence of several metal ions were analysed in MeCN/H2 O (1 : 4 v/v) solutions. A selective chelation enhancement of fluorescence (CHEF) effect was observed in the presence of Zn2+ in the case of L1, and in the presence of Cd2+ in the case of L2, following the formation of a 1 : 1 and a 1 : 2 metal/ligand complex, respectively, which was also confirmed by potentiometric measurements. 1 H and 13 C NMR measurements in CD3 CN/CDCl3 in combination with molecular mechanics calculations show that for both complexes of L1 and L2 with Zn2+ and Cd2+ , respectively, the coordination of the carbonyl group from the pendant arm could be the origin of the observed optical selectivity.

Switching on the Fluorescence Emission of Polypyridine Ligands by Simultaneous Zinc(II) Binding and Protonation.

The synthesis and characterization of the two new open-chain ligands 1,15-bis-[6-(2,2'-bipyridyl)]-2,5,8,11,14-pentaaza-octadecane (L1) and 1,15-bis-[2-(1,10-phenanthroline)-9-methyl]-2,5,8,11,14-pentaazaoctadecane (L2), both featuring a tetraethylenpentaamine chain linking via methylene bridges the 6 and 2 positions of two identical 2,2'-bipyridyl (bpy) and 9-methyl-1,10-phenanthroline (9-methyl-phen) moieties respectively, are reported. Their protonation and binding ability for Cu2+ , Zn2+ , Cd2+ and Pb2+ have been studied by coupling potentiometric titrations with UV-vis absorption and fluorescence emission measurements in water. L1 and L2 afford stable mono- and dinuclear complexes, in which the metal ion is bound by a single bpy or 9-methyl-phen unit and the amine groups on the aliphatic chain. However, L1 displays a greater binding ability for Cu2+ and Zn2+ with respect to L2, the stability constants of the [ML1]2+ complexes being 21.8 (Cu2+ ) and 19.4 (Zn2+ ) log units vs 20.34 and 16.8 log. units for the corresponding L2 species. Among all the metal ions tested, only the Zn2+ complex with L2 features an enhanced fluorescence emission at neutral pH, thanks to the simultaneous binding of one Zn2+ ion and H+ ion(s), that inhibits any possible photoinduced electron transfer (PET) process from the amine donors to the excited phen moiety. Binding of a second metal switches off the emission again.

Different Antioxidant Efficacy of Two MnII-Containing Superoxide Anion Scavengers on Hypoxia/Reoxygenation-Exposed Cardiac Muscle Cells.

Oxidative stress due to excess superoxide anion ([Formula: see text]) produced by dysfunctional mitochondria is a key pathogenic event of aging and ischemia-reperfusion diseases. Here, a new [Formula: see text]-scavenging MnII complex with a new polyamino-polycarboxylate macrocycle (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetate) containing 2 quinoline units (MnQ2), designed to improve complex stability and cell permeability, was compared to parental MnII complex with methyls replacing quinolines (MnM2). MnQ2 was more stable than MnM2 (log K = 19.56(8) vs. 14.73(2) for the equilibrium Mn2+ + L2-, where L = Q2 and M2) due to the involvement of quinoline in metal binding and to the hydrophobic features of the ligand which improve metal desolvation upon complexation. As oxidative stress model, H9c2 rat cardiomyoblasts were subjected to hypoxia-reoxygenation. MnQ2 and MnM2 (10 µmol L-1) were added at reoxygenation for 1 or 2 h. The more lipophilic MnQ2 showed more rapid cell and mitochondrial penetration than MnM2. Both MnQ2 and MnM2 abated endogenous ROS and mitochondrial [Formula: see text], decreased cell lipid peroxidation, reduced mitochondrial dysfunction, in terms of efficiency of the respiratory chain and preservation of membrane potential (Δψ) and permeability, decreased the activation of pro-apoptotic caspases 9 and 3, and increased cell viability. Of note, MnQ2 was more effective than MnM2 to exert cytoprotective anti-oxidant effects in the short term. Compounds with redox-inert ZnII replacing the functional MnII were ineffective. This study provides clues which further our understanding of the structure-activity relationships of MnII-chelates and suggests that MnII-polyamino-polycarboxylate macrocycles could be developed as new anti-oxidant drugs.

Highly Charged Ruthenium(II) Polypyridyl Complexes as Effective Photosensitizer in Photodynamic Therapy.

A comparative study between two novel, highly water soluble, ruthenium(II) polypyridyl complexes, [Ru(phen)2 L'] and [Ru(phen)2 Cu(II)L'] (L and L-CuII ), containing the polyaazamacrocyclic unit 4,4'-(2,5,8,11,14-pentaaza[15])-2,2'-bipyridilophane (L'), is herein reported. L and L-CuII interact with calf-thymus DNA and efficiently cleave DNA plasmid when light-activated. They also possess great penetration abilities and photo-induced biological activities, evaluated on an A375 human melanoma cell line, with L-CuII being the most effective. Our study highlights the key role of the Fenton active CuII center within the macrocycle framework, that would play a synergistic role with light activation in the formation of cytotoxic ROS species. Based on these results, an optimal design of RuII polypyridyl systems featuring specific CuII -chelating polyamine units could represent a suitable strategy for the development of novel and effective photosensitizers in photodynamic therapy.

[9]aneN3-based fluorescent receptors for metal ion sensing, featuring urea and amide functional groups.

We describe here the synthesis and coordination properties of three new derivatives of [9]aneN3 containing phenyl/quinoline pendant arm derivatives (L1, L2 and L3, respectively) also featuring urea (L1-L2) or amide (L3) functions as "non-innocent" spacers. At first, L1, L2 and L3 were studied considering the interaction with a series of anions (AcO-, BzO-, H2PO4-, F-, and Cl-) by means of 1H NMR measurements. Subsequently, the optical responses of L2 and L3 in the presence of several metal ions Cd2+, Co2+, Cu2+, Fe3+, Hg2+, K+, Mg2+, Mn2+, Ni2+, Zn2+ and Pb2 were analysed in MeCN/H2O (4 : 1 v/v). As observed by spectrophotometric and spectrofluorimetric titrations, there were significant changes in the absorbance and fluorescent emission of L2 upon addition of increasing amounts of Cd2+, Zn2+, Pb2+ and Cu2+ in MeCN/H2O (4 : 1 v/v). In particular, titrations of L2 with Cd2+, Zn2+ or Pb2+ showed an almost comparable CHEF effect up to an M2+/L2 molar ratio of 1. Overall, no significant optical selectivity was observed in the case of L2. Conversely, L3 revealed an OFF-ON selective response only in the presence of the Zn2+ ion in MeCN/H2O (4 : 1 v/v), which can be attributed to the formation of both 1 : 1 and 1 : 2 metal-to-ligand complexes, as also confirmed by potentiometric measurements. Finally, crystals of [ZnL1(Ac)](Ac) (1), [CuL1(Cl)](Cl)·H2O (2) and [CuL3](NO3) (3) were grown and analysed by X-ray diffraction. 1 and 3 feature the metal center in a pseudo-octahedral coordination geometry coordinated also by the carbonyl group from one pendant arm, while in the case of 2, one of the six coordination sites in the final distorted octahedral geometry is occupied by the nitrogen donor from the urea group of one pendant arm.

The solid-state structure of the ß-blocker metoprolol: a combined experimental and in silico investigation.

Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective ß1-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other ß-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other ß-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O-H...N/N...H-O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O...H-N/N-H...O pair of interactions. In addition, within the same stack of molecules, a C-H...O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the ß-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.

Fluoride binding by an anionic receptor: tuning the acidity of amide NH groups for basic anion hydrogen bonding and recognition.

Here we report a family of bis-amide receptors for anion binding that contain carboxylic acid groups vicinal to the amide function. Deprotonation of the carboxylic acids decreases the acidity of amide NHs, switching on the anion binding ability of the deprotonated receptors with selectivity for fluoride complexation. The proposed systems represent a unique example of anionic receptors able to bind anions via H-bonding.

A Fluorescent Silver(I) Carbene Complex with Anticancer Properties: Synthesis, Characterization, and Biological Studies.

The silver(I) N-heterocyclic carbene (NHC) complex bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride ([Ag(EIA)2 ]Cl), bearing two anthracenyl fluorescent probes, has been synthesized and characterized. [Ag(EIA)2 ]Cl is stable in organic solvents and under physiological conditions, and shows potent cytotoxic effects in vitro toward human SH-SY5Y neuroblastoma cells. The interactions of [Ag(EIA)2 ]Cl with a few model biological targets have been studied as well as its ability to be internalized in cells. The in vitro anticancer activity is apparently related to the level of drug internalization. Notably, [Ag(EIA)2 ]Cl does not react with a few model proteins, but is capable of binding the C-terminal dodecapeptide of thioredoxin reductase hTrxR(488-499) and to strongly inhibit the activity of this enzyme. Binding occurs through an unconventional process leading to covalent binding of one or two carbene ligands to the C-terminal dodecapeptide with concomitant release of the silver cation. To the best of our knowledge, this mode of interaction is reported here for the first time for Ag(NHC)2 complexes.

Spectroscopic and photoacoustic characterization of encapsulated iron oxide super-paramagnetic nanoparticles as a new multiplatform contrast agent.

Recently, a number of photoacoustic (PA) agents with increased tissue penetration and fine spatial resolution have been developed for molecular imaging and mapping of pathophysiological features at the molecular level. Here, we present bio-conjugated near-infrared light-absorbing magnetic nanoparticles as a new agent for PA imaging. These nanoparticles exhibit suitable absorption in the near-infrared region, with good photoacoustic signal generation efficiency and high photo-stability. Furthermore, these encapsulated iron oxide nanoparticles exhibit strong super-paramagnetic behavior and nuclear relaxivities that make them useful as magnetic resonance imaging (MRI) contrast media as well. Their simple bio-conjugation strategy, optical and chemical stability, and straightforward manipulation could enable the development of a PA probe with magnetic and spectroscopic properties suitable for in vitro and in vivo real-time imaging of relevant biological targets.

Methylene blue-containing liposomes as new photodynamic anti-bacterial agents.

Methylene blue (MB) can be employed as a photo-activatable antimicrobial drug in photodynamic therapy (PDT) due to its ability to release oxygen free radicals upon photo-activation. However, its poor ability to penetrate bacterial cell walls and bacterial biofilms limits its antimicrobial activity. To overcome these limitations, we propose some formulations of MB based on different cationic liposomes. The liposome-MB systems were characterized using dynamic light scattering (DLS), zeta potential analysis and UV-visible spectroscopy. Their ability to penetrate inside the cytoplasm of E. coli, taken as a bacterial model for Gram-negative strains, was investigated through laser scanning confocal microscopy (CLSM) and compared to the penetration of naked MB. Then, MB-loaded liposomes were photo-activated and their antimicrobial activity was tested against E. coli, showing a strong improvement with respect to MB solutions. The liposomal formulations dramatically enhance MB penetration in bacterial biofilms and reduce the inflammatory response due to lipopolysaccharide exposure in mammalian cells. The observed antimicrobial and anti-inflammatory efficacies show a clear correlation with some structural features of the carriers, namely the size and the surface charge density. Overall, these results provide fundamental knowledge that enables the design of novel efficient PDT treatments, which potentially overcome the rising incidence of antibiotic resistance of bacterial strains.

Catching anions with coloured assemblies: binding of pH indicators by a giant-size polyammonium macrocycle for anion naked-eye recognition.

A giant-size polyamine macrocycle L, composed of four 1,4,8,11-tetraazacyclotetradecane (cyclam) units linked by 1,3-dimethylenbenzyl spacers, strongly interacts in aqueous solution with four pH indicators (bromocresol purple (H2BCP), phenol red (H2PR), phenolphthalein (H2PP) and fluorescein (H2F)) in their anionic forms. Besides 1 : 1 complexes, L also forms assemblies with an unusual 1 : 2 receptor to dye stoichiometry, thanks to its large dimensions, which allow for the simultaneous interaction of the receptor protonated forms with two anionic dyes. The formation of the assemblies markedly affects the pKa values of the phenol groups of the dyes, which change colour upon complexation in well-defined pH ranges. This property can be effectively exploited for optical detection of anions. The L-H2BCP 1 : 2 assembly is able to selectively detect the triphosphate anion at slightly acidic pH values, thanks to the release, upon triphosphate coordination, of the dye from the ensemble, with a consequent colour change of the solution from purple-violet (complexed BCP(2-) dye) to yellow (free BCP(2-)). No effect is caused by other inorganic anions. The L-H2BCP 1 : 2 assembly represents a rare case of an optical chemosensor for the triphosphate anion.

Metal-based optical chemosensors for CN- detection.

This critical review focuses on recent advances (2010-2015) in the detection of cyanide anion via metal-based optical chemosensors in which a change in colour and/or fluorescence intensity (or emission wavelength) of a molecular metal complex is determined by the direct interaction of the metal centre with this anion.

Di- and Triphosphate Recognition and Sensing with Mono- and Dinuclear Fluorescent Zinc(II) Complexes: Clues for the Design of Selective Chemosensors for Anions in Aqueous Media.

The synthesis of a new ligand (L1) containing two 1,4,7-triazacyclononane ([9]aneN3 ) moieties linked by a 4,5-dimethylenacridine unit is reported. The binding and fluorescence sensing properties toward Cu2+ , Zn2+ , Cd2+ , and Pb2+ of L1 and receptor L2, composed of two [9]aneN3 macrocycles bridged by a 6,6''-dimethylen-2,2':6',2''-terpyridine unit, have been studied by coupling potentiometric, UV/Vis absorption, and emission measurements in aqueous media. Both receptors can selectively detect Zn2+ thanks to fluorescence emission enhancement upon metal binding. The analysis of the binding and sensing properties of the Zn2+ complexes toward inorganic anions revealed that the dinuclear Zn2+ complex of L1 selectively binds and senses the triphosphate anion (TP), whereas the mononuclear Zn2+ complex of L2 displays selective recognition of diphosphate (DP). Binding of TP or DP induces emission quenching of the Zn2+ complexes with L1 and L2, respectively. These results are exploited to discuss the role played by pH, number of coordinated metal cations, and binding ability of the bridging units in metal and/or anion coordination and sensing.