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Metal complexes have gained a huge interest in the biomedical research in the last decade because of the access to unexplored chemical space with regards to organic molecules and to present additional func-tionalities to act simultaneously as diagnostic and therapeutic agents. Herein, we evaluated the interaction of two polytopic polyaza ligands and their zinc complexes with DNA and RNA by UV thermal denatura-tion, fluorescence and circular dichroism spectroscopic assays. The zinc coordination was investigated by X-ray diffraction and afforded the structure of the binuclear zinc complex of PYPOD. Thermal denaturation of DNA and RNA and fluorimetry analysis revealed preferential binding of the zinc-PHENPOD complexes towards GC-containing DNA in contrast to the free ligands. On the other hand, PYPOD metal complexes, compared to the free ligand, stabilized AT-based DNA (B-form) better than AU-RNA (A-form). With regards to single stranded RNA, the binuclear complex of PHENPOD and the free ligand can efficiently identify polyadenylic acid (poly A) among other RNA sequences by circular dichroism spectroscopy. The antimicrobial activity in S. aureus and E. coli bacteria showed the highest activity for the free ligands and their trinuclear zinc complexes. This work can provide valuable insights into the impact of the nucle-arity of polytopic polyaza ligands in the binding to DNA/RNA and the antimicrobial effect.

Two oxoiron(IV) isomers (R2a and R2b) of general formula [FeIV(O)(RPyNMe3)(CH3CN)]2+ are obtained by reaction of their iron(II) precursor with NBu4IO4. The two isomers differ in the position of the oxo ligand, cis and trans to the pyridine donor. The mechanism of isomerization between R2a and R2b has been determined by kinetic and computational analyses uncovering an unprecedented path for interconversion of geometrical oxoiron(IV) isomers. The activity of the two oxoiron(IV) isomers in hydrogen atom transfer (HAT) reactions shows that R2a reacts one order of magnitude faster than R2b, which is explained by a repulsive noncovalent interaction between the ligand and the substrate in R2b. Interestingly, the electronic properties of the R substituent in the ligand pyridine ring do not have a significant effect on reaction rates. Overall, the intrinsic structural aspects of each isomer define their relative HAT reactivity, overcoming changes in electronic properties of the ligand.

In Myotonic Dystrophy type 1 (DM1), a non-coding CTG repeats rare expansion disease; toxic double-stranded RNA hairpins sequester the RNA-binding proteins Muscleblind-like 1 and 2 (MBNL1 and 2) and trigger other DM1-related pathogenesis pathway defects. In this paper, we characterize four d-amino acid hexapeptides identified together with abp1, a peptide previously shown to stabilize CUG RNA in its single-stranded conformation. With the generalized sequence cpy(a/t)(q/w)e, these related peptides improved three MBNL-regulated exon inclusions in DM1-derived cells. Subsequent experiments showed that these compounds generally increased the relative expression of MBNL1 and its nuclear-cytoplasmic distribution, reduced hyperactivated autophagy, and increased the percentage of differentiated (Desmin-positive) cells in vitro. All peptides rescued atrophy of indirect flight muscles in a Drosophila model of the disease, and partially rescued muscle function according to climbing and flight tests. Investigation of their mechanism of action supports that all four compounds can bind to CUG repeats with slightly different association constant, but binding did not strongly influence the secondary structure of the toxic RNA in contrast to abp1. Finally, molecular modeling suggests a detailed view of the interactions of peptide-CUG RNA complexes useful in the chemical optimization of compounds.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro and in vivo models of HD. Activation of these pathways degrades mHtt and other protein-containing polyQs, which restores proteostasis in these models. Hence, we propose 4QMn as a potential drug to develop a therapy to treat HD.

Green catalysts with excellent performance in Cu-free Sonogashira coupling reactions can be prepared by the supramolecular decoration of graphene surfaces with Pd(II) complexes. Here we report the synthesis, characterization, and catalytic properties of new catalysts obtained by the surface decoration of multiwalled carbon nanotubes (MWCNTs), graphene (G), and graphene nanoplatelets (GNPTs) with Pd(II) complexes of tetraaza-macrocyclic ligands bearing one or two anchor functionalities. The decoration of these carbon surfaces takes place under environmentally friendly conditions (water, room temperature, aerobic) in two steps: (i) π-π stacking attachment of the ligand via electron-poor anchor group 6-amino-3,4-dihydro-3-methyl-5-nitroso-4-oxo-pyrimidine and (ii) Pd(II) coordination from PdCl

In the presence of Ag(I), the monoanion of cyano-N-squaraine (I) generates an intense fluorescence turn-on response. Experimental evidence and DFT calculations reveal a sequence of deprotonation-coordination events in which the Ag(I) ions play a dual role as a Lewis acid and coordinating metal. The observed effect is highly selective for Ag(I) compared to other metals.

[EN] Enzymatic browning is one of the main problems faced by the food industry due to the enzyme polyphenol oxidase (PPO) provoking an undesirable color change in the presence of oxygen. Here, we report the evaluation of 10 different azamacrocyclic compounds with diverse morphologies as potential inhibitors against the activity of PPO, both in model and real systems. An initial screening of 10 ligands shows that all azamacrocyclic compounds inhibit to some extent the enzymatic browning, but the molecular structure plays a crucial role on the power of inhibition. Kinetic studies of the most active ligand (L2) reveal a S-parabolic I-parabolic noncompetitive inhibition mechanism and a remarkable inhibition at micromolar concentration (IC50 = 10 mu M). Furthermore, L2 action has been proven on apple juice to significantly reduce the enzymatic browning., Financial support by the Spanish Ministerio de Ciencia, Innovacion y Universidades (project RTI2018-100910-B-C44), Ministerio de Economia y Competitividad (projects CTQ2016-78499-C6-1-R, Unidad de Excelencia MDM 2015-0038 and CTQ2017-90852-REDC), and Generalitat Valenciana (Project PROMETEOII2015-002) is gratefully acknowledged.

We report the synthesis and characterization of the macrocyclic ligand 2,2'-((2-(3,9-bis(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-6-yl)ethyl)azanediyl)diacetic acid (H4L) and several of its complexes with lanthanide ions. The structure of the free ligand was determined using X-ray diffraction measurements. Two N atoms of the pyclen moiety in the trans position are protonated in the solid state, together with the exocyclic N atom and one of the carboxylate groups of the ligand. The relaxivity of the Gd3+ complex was found to increase from 6.7 mM-1 s-1 at pH 8.6 to 8.5 mM-1 s-1 below pH ≈ 6.0. Luminescence lifetime measurements recorded from H2O and D2O solutions of the Eu3+ complex evidence the presence of a single complex species in solution at low pH (∼5.0) that contains two inner-sphere water molecules. DFT calculations suggest that the coordination environment of the Ln3+ ion is fulfilled by the four N atoms of the pyclen unit, two oxygen atoms of the macrocyclic acetate groups, and an oxygen atom of an exocyclic carboxylate group. The two inner-sphere water molecules complete coordination number nine around the metal ion. At high pH (∼9.3), the lifetime of the excited 5D0 level of Eu3+ displays a biexponential behavior that can be attributed to the presence of two species in solution with hydration numbers of q = 0 and q = 1. The 1H NMR and DOSY spectra recorded from solutions of the Eu3+ and Y3+ complexes reveal a structural change triggered by pH and the formation of small aggregates at high pH values.

A novel amino-nanozyme, based on boehmite nanoparticles (BNPs) functionalised with a tetra-azapyridinophane (L1), has been designed to undermine some of the key issues underlying Huntington disease. L1 forms Cu2+ complexes with a striking SOD activity, while when grafted to the BNPs displays mitoROS scavenging properties and ability to disaggregate mutant huntingtin deposits in cells.

Three ligands bearing triphenylamine as a core and one, two or three acyclic polyamine chains, TPA1p, TPA2p and TPA3p, respectively, have been studied by potentiometric and photophysical (UV-Vis, steady-state and time-resolved fluorescence) techniques. The host-guest interaction with cucurbit[7]uril, CB7, has been investigated in aqueous solution showing aggregation induced emission behaviour when encapsulated into a CB7 cavity. From fluorescence emission it is revealed that the charged polyamine chains are the unit entering into CB7 and from the Job plots the stoichiometries are found to vary from 1 : 1 to 1 : 3 L : CB7 ratios. Interactions of the charged amines with the portals of CB7 restrict rotation of the benzene units in the triphenylamine backbone (free rotor effect), decreasing the radiationless internal conversion channel at the expense of the enhancement of fluorescence. Dynamic light scattering and resonance Rayleigh scattering experiments show that TPA3p-CB7 complexes involve formation of aggregates with a mean size of 126 ± 5 nm and a dispersity factor of 0.117, indicating a monodisperse distribution and supporting the important conclusions of this work: formation of emissive aggregates through the AIE effect.

Polyiodide networks are currently of great practical interest for the preparation of new electronic materials. The participation of metals in the formation of these networks is believed to improve their mechanical performance and thermal stability. Here we report the results on the construction of polyiodide networks obtained using Cu(II) complexes of a series of pyridinol-based tetraazacyclophanes as countercations. The assembly of these crystalline polyiodides takes place from aqueous solutions on the basis of similar structural elements, the [CuL]2+ and [Cu(H–1L)]+ (L = L2, L2-Me, L2-Me3) complex cations, so that the peculiarities induced by the increase of N-methylation of ligands, the structural variable of ligands, can be highlighted. First, solution equilibria involving ligands and complexes were analyzed (potentiometry, NMR, UV–vis, ITC). Then, the appropriate conditions could be selected to prepare polyiodides based on the above complex cations. Single-crystal XRD analysis showed that the coordination of pyridinol units to two metal ions is a prime feature of these ligands, leading to polymeric coordination chains of general formula {[Cu(H–1L)]}nn+ (L = L2-Me, L2-Me3). In the presence of the I–/I2 couple, the polymerization tendency stops with the formation of [(CuL)(CuH–1L)]3+ (L = L2-Me, L2-Me3) dimers which are surrounded by polyiodide networks. Moreover, coordination of the pyridinol group to two metal ions transforms the surface charge of the ring from negative to markedly positive, generating a suitable environment for the assembly of polyiodide anions, while N-methylation shifts the directional control of the assembly from H-bonds to I···I interactions. In fact, an extended concatenation of iodine atoms occurs around the complex dimeric cations, the supramolecular I···I interactions become shorter and shorter, fading into stronger forces dominated by the orbital overlap, which is promising for effective electronic materials., Polyiodides with high iodine density are generated by Cu(II) complexes of pyridinol-based tetraazacyclophanes. Direct coordination of iodine atoms to Cu(II), anion−π interactions with electron-poor aromatic surfaces, and shift of the directional control of assembly from H-bonds to I···I interactions, governed by N-methylation, are the main elements leading to enhanced iodine chaining and strengthening of I···I contacts.

Leishmaniasis is one of the world's most neglected diseases with a worldwide prevalence of 12 million people. There are no effective human vaccines for its prevention, and outdated drugs hamper treatment. Therefore, research aimed at developing new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, here, we present 10 new compounds made up by linking alkylated ethylenediamine units to pyridine or quinoline heterocycles with promising in vitro and in vivo efficacy against promastigote and amastigote forms of Leishmania infantum, Leishmania donovani, and Leishmania braziliensis species. Three compounds (2, 4, and 5) showed a selectivity index much higher in the amastigote form than the reference drug glucantime. These three derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC25 dose. In addition, these derivatives were substantially more active against the three Leishmania species tested than glucantime. The mechanism of action of these compounds has been studied, showing alterations in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy due to their effectiveness and their ready synthesis.

Currently, significant efforts are devoted to designing small molecules able to bind selectively to guanine quadruplexes (G4s). These noncanonical DNA structures are implicated in various important biological processes and have been identified as potential targets for drug development. Previously, a series of triphenylamine (TPA)-based compounds, including macrocyclic polyamines, that displayed high affinity towards G4 DNA were reported. Following this initial work, herein a series of second-generation compounds, in which the central TPA has been functionalised with flexible and adaptive linear polyamines, are presented with the aim of maximising the selectivity towards G4 DNA. The acid-base properties of the new derivatives have been studied by means of potentiometric titrations, UV/Vis and fluorescence emission spectroscopy. The interaction with G4s and duplex DNA has been explored by using FRET melting assays, fluorescence spectroscopy and circular dichroism. Compared with previous TPA derivatives with macrocyclic substituents, the new ligands reported herein retain the G4 affinity, but display two orders of magnitude higher selectivity for G4 versus duplex DNA; this is most likely due to the ability of the linear substituents to embrace the G4 structure.

Three new [1 + 1] macrocycles formed by the reaction of 1H-3,5-bis(chloromethyl)pyrazole with the tosylated amines 1,4,7,10-tetraazadecane (L1), 1,4,8,11-tetraazaundecane (L2) and 1,5,10,14-tetraazatetradecane (L3) are described. Potentiometric studies and HR-ESI-Mass spectrometry show the formation of dimeric binuclear Cu2+ complexes whose organization depends on the type of hydrocarbon chains connecting the amine groups. Furthermore, trinuclear or/and tetranuclear complexes are formed depending also on the length of the polyaminic bridge and on the sequence of the hydrocarbon chains. The crystal structures of the [2 + 2] [Cu2(H(H−1L2))2](ClO4)4·4H2O (1) and [Cu2(H−1L2)2](ClO4)2 (2) complexes show in both of them two macrocycles self-assembled by the metal ions which interconnect their pyrazolate fragments that behave as bis(monodentate) ligands. While in 1 one central amine of each macrocycle binds to the axial position of a distorted square-pyramid and the other ones remain protonated, in 2 all the amine groups are involved in the coordination giving rise to a strongly distorted octahedral geometry. Paramagnetic 1H NMR measurements support that these structures also form in solution. Interestingly, tetranuclear complexes [Cu4(H−1L4)2(OH)2.08](ClO4)2.92Br0.54Cl0.46 (3) and [Pd2.39Cu1.61(H−1L4)2(OH)2](ClO4)2Cl1.33Br0.67·2.87H2O (4) have been isolated for the macrocycle containing the 1,5,9,13-tetraamine chain (L4). 3 has two binucleating units, one of them formed by the pyrazolate moieties and their neighbouring secondary amines and the other by the two central amines of both macrocycles. This latter Cu2+ coordination site is completed by two hydroxide anions as bridging ligands. 4 was obtained from a solution prepared to achieve full formation of the dimeric cage [Cu2(H−1(HL4))2]4+ by addition of K2PdCl4. The Pd2+ ion due to its softer acidic characteristics displaces the Cu2+ ions from the pyrazolate site. UV-vis spectroscopy suggests that the exchange is completed at room temperature after one hour.

Here we present the preparation and characterization of new biocompatible materials for drug encapsulation. These new gels are based on positively charged [1+1] 1H-pyrazole-based azamacrocycles which minimise the electrostatic repulsions between the negatively charged GMP molecules. Rheological measurements confirm the electroneutral hydrogel structure as the most stable for all the GMP-polyamine systems. Nuclear magnetic resonance (NMR) was employed to investigate the kinetics of the hydrogel formation and cryo-scanning electron microscopy (cryo-SEM) was used to obtain information about the hydrogel morphology, which exhibited a non-homogeneous structure with a high degree of cross-linking. It is possible to introduce isoniazid, which is the most employed antibiotic for tuberculosis treatment, into the hydrogels without disrupting the hydrogel structure at appropriate concentrations for oral administration.

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.

Ordered polyiodide networks have recently gathered considerable attention as electronic materials, a topic historically dominated by metals. Could we incorporate metal cations into polyiodide frameworks in a controlled manner to simultaneously boost electronic properties and robustness of these materials? Herein we present a first principles study featuring three analogous polyazacyclophanes (L, L-Me, L-Me3), differing only in the extent of N-methylation. We demonstrate (potentiometry, ITC) how they all form the same CuL2+ (L = L, L-Me, L-Me3) complex as prevalent species in solution, so that a level playing field exists where only N-methylation distinguishes them. Then we use them as countercations for polyiodide growth. XRD analysis of the resulting crystals clearly shows that methylation is a valuable tool to gradually shift directional control of subtending pairing preferences from H-bond to I⋯I interactions: this affects global packing and actively incorporates metal centres into polyiodide chains, setting the scene for further developments.

Triazolopyridine-pyridine amine ligands are easily obtained by means of either thermal- or copper(II)-mediated reactions. Starting from a readily accessible iodo derivative of triazolopyridine-pyridine and different amines, this new family of compounds combines aromatic and aliphatic nitrogen atoms with promising coordinating properties. Furthermore, chemical derivatization of a new triazolopyridine-pyridine diamine compound, N1-[6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)pyridin-2-yl]ethan-1,2-diamine, allows the preparation of several remote-pyridine-containing ligands.

In the presence of Ag(i), the monoanion of cyano-N-squaraine (I) generates an intense fluorescence turn-on response. Experimental evidence and DFT calculations reveal a sequence of deprotonation-coordination events in which the Ag(i) ions play a dual role as a Lewis acid and coordinating metal. The observed effect is highly selective for Ag(i) compared to other metals.

A self-assembled metallobox from copper(ii) and two macrocycles containing 1H-pyrazole ligands has been prepared. The internal cavity of the box is able to selectively encapsulate a single chloride anion over any other halide anion.

A wide range of organic ligands are found in the rhizosphere. Two important groups are low-molecular-weight organic acids (LMWOAs) and siderophores. We know that LMWOAs and siderophores coexist in the rhizosphere and it has been proposed that they interact, but it is not clear what controls this. Such knowledge gaps undermine biofortification efforts. In this study test the hypothesis that pH and ionic strength gradients make it possible for LMWOAs and siderophores to function synergistically during micronutrient cycling in the rhizosphere.

Anion-π interactions are emerging as exotic features with potential applications in chemistry. In the last years, their relevance in living systems has been outlined, and so far there is no concluding significant evidence recognized about the participation of anion-π interactions in water because anion-π sensors contain large aromatic hydrophobic surfaces with limited solubility. By transforming a neutral heterocycle (for example quinoline) into its corresponding salt (quinolinium), we have been able to overcome these solubility issues, and new cationic water-soluble fluorophores have been prepared. Herein, we used N-alkylated heterocycles as π-acidic surfaces to shed light on the nature of anion-π in water by the direct measurement of the fluorescence and UV/Vis spectra in combination with DFT and X-ray analyses.

The synthesis of four dirhenium(III) cis-dicarboxylates with the α-amino acids residues Asp (I), Glu (II), Phe (III) and Tyr (IV) is presented. The G-quadruplex stabilization potential was evaluated by fluorescence resonance energy transfer - melting analysis. All derivatives show specific binding to c-kit1 quadruplex, while II and IV have also strong stabilization activity to HTelo21 quadruplex. At the same time, the compounds do not show any stabilization activity for ds26 DNA, which suggests unique mechanisms of molecular DNA recognition for these complexes.

Non-traditional stable isotope systems are increasingly used to study micronutrient cycling and acquisition in terrestrial ecosystems. We previously proposed for zinc (Zn) a conceptual model linking observed isotope signatures and fractionations to biogeochemical processes occurring in the rice soil environment and we suggested that 2’deoxymugineic acid (DMA) could play an important role for rice during the acquisition of Zn when grown under Zn limiting conditions. This proposition was sustained by the extent and direction of isotope fractionation observed during the complexation of Zn with DMA synthesised in our laboratory. Here we report a new set of experimental data from field and laboratory studies designed to further elucidate the mechanisms controlling Zn isotope fractionation in the rice rhizosphere and the role of DMA. First, we present acidity (pKa) and complexation (logK) constants for DMA with H+ and Zn2+, respectively, using synthetic 2’deoxymugineic acid and show that they are significantly different from previously published data using isolates from plants. Our new set of thermodynamic data allows for a more accurate calculation of the formation of ZnDMA complexes over pH ranges typically found in the rhizosphere of flooded lowland rice soils and in rice plant compartments (xylem, phloem). We show that at pH > 6.5, Zn is fully complexed by DMA and at pH 0) detected during adsorption of Zn on goethite in alkaline solutions or between root and soil solution in rice grown in alkaline soils. We show that removal of different Zn species from solution and changes in the Zn coordination control extent and direction of isotope fraction during adsorption. Using the new set of results and combining it with recent findings from the literature, we present a refined conceptual model linking biogeochemical processes to Zn isotope fractionation in the rice soil system. Our results confirm the importance of root induced chemical changes in the rhizosphere of rice growing in soils with low Zn availability, demonstrate the unique ability of isotope signatures to deconvolve geochemical processes and conditions in the plant-soil environment and support the hypothesis of an important role of DMA in Zn acquisition under Zn limiting conditions.

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.