Search

The Cu(ii)–HPH-NH2 and Cu(ii)–HPHPY-NH2 systems were proved to be relevant functional models of LPMOs, even at neutral pH.

The terminal N-mono- and dimethylated derivatives of an estrone–salicylaldehyde thiosemicarbazone hybrid and their highly cytotoxic Cu(II) complexes were synthesized and characterized in addition to their structurally related simpler bicyclic analogues. Solution stability and structure of the complexes were determined by UV–visible spectrophotometry and electron paramagnetic resonance spectroscopy. The monomethylation has a minor influence on the pKa values, while the dimethylation results in somewhat more acidic derivatives compared to the non-methylated derivatives, although all the compounds are neutral at physiological pH. Based on the speciation studies performed in a 30% (v/v) dimethyl sulfoxide/water mixture, the four novel ligands form fairly high-stability complexes with Cu(II) ions, in which they coordinate in mono-anionic (O‒,N,S) or di-anionic (O‒,N,S‒) binding modes. [CuLH‒1] species with (O‒,N,S‒)(H2O) coordination mode are present in solution at neutral pH, and these complexes were isolated and further studied. The Cu(II) complexes formed with the estrone hybrids were more stable in comparison with the bicyclic analogues. The terminal N-dimethylation results in the most stable complexes in a given ligand series. In vitro cytotoxicity of all the Cu(II) complexes was measured in 3D spheroids of HCT-116, A-549 and CH-1 human cancer cells which showed fairly low IC50 values (3.9‒17.1 μM). The Cu(II) complexes caused reduced tumour growth, and they activated the caspase-3 and caspase-7 endoproteases leading to apoptosis except the case of the complex formed with the monomethylated bicyclic derivative, where other type of mechanisms of action seems to induce the cell death. Anticancer Cu(II) complexes of mono- and dimethylated salicylaldehyde thiosemicarbazone-estrone hybrids possessing high solution stability and strong cytotoxic effect against 3D spheroids of a series of human cancer cells. 398x273 mm (150 x 150 DPI)

COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe2 and COTI-NMeCy), and the non-substituted analogue (COTI-NH2) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe2 as an interesting new drug candidate with improved anticancer activity and resistance profile.

Copper(II) complexes formed with sulfonated salan ligands (HSS) have been synthesized, and their coordination chemistry has been characterized using pH-potentiometry and spectroscopic methods [UV-vis, electron paramagnetic resonance (EPR), and electron-electron double resonance (ELDOR)-detected NMR (EDNMR)] in aqueous solution. Several bridging moieties between the two salicylamine functions were introduced, e.g., ethyl (HSS), propyl (PrHSS), butyl (BuHSS), cyclohexyl (cis-CyHSS, trans-CyHSS), and diphenyl (dPhHSS). All of the investigated ligands feature excellent copper(II) binding ability via the formation of a (O-,N,N,O-) chelate system. The results indicated that the cyclohexyl moiety significantly enhances the stability of the copper(II) complexes. EPR studies revealed that the arrangement of the coordinated donor atoms is more symmetrical around the copper(II) center and similar for HSS, BuHSS, CyHSS, and dPhHSS, respectively, and a higher rhombicity of the g tensor was detected for PrHSS. The copper(II) complexes of the sulfosalan ligands were isolated in solid form also and showed moderate catalytic activity in the Henry (nitroaldol) reaction of aldehydes and nitromethane. The best yield for nitroaldol production was obtained for copper(II) complexes of PrHSS and BuHSS, although their metal binding ability is moderate compared to that of the cyclohexyl counterparts. However, these complexes possess larger spin density on the nitrogen nuclei than that for the other cases, which alters their catalytic activity.

The Cu2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV–vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV–vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+–Cu2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+ complexes in aqueous solution were investigated by UV–vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+ to Cu+ on the CV time scale. The Cu+ complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+ and Cu+ complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+., A series of cyclen derivatives bearing sulfur- or mixed-sulfur-carboxylated pendant arms were considered as chelators for copper radioisotopes in radiopharmaceuticals. Stability and structure of their Cu2+ and Cu+ complexes were studied in aqueous solution using a multimethodological approach. The stability of both Cu2+ and Cu+ complexes should prevent the reductive-based copper demetallation observed in vivo for other copper chelators.

Solution speciation of Rh(η5-C5Me5), Ru(η6-p-cymene) and Ru(η6-toluene) complexes of 2,4-pyridinedicarboxylic acid (2,4-dipicH2) was studied and compared to that of 2-picolinic acid (picH) in addition to their reactivity towards chloride and bromide ions, 1-methylimidazole and guanosine. Structures of [Rh(η5-C5Me5)(2,4-dipicH)Cl] ⋅ 3H2O (1), 2[Ru(η6-toluene)(2,4-dipicH)Cl] ⋅ 3H2O (2) and [Ru(η6-toluene)(2,4-dipic)]3 ⋅ 7H2O (3) were analyzed by X-ray diffraction. 1 and 2 show typical piano stool geometry, while 3 is a triangular complex stabilized via the monodentate coordination of the second carboxylate group to the neighboring Ru(II) center. High stability [M(arene)L(H2O/Cl)] species predominate at pH 7.4. 2,4-Dipic forms more stable complexes with Ru(η6-arene) than pic, with this difference being minor in the case of the Rh(η5-C5Me5) complexes. A lower affinity of 2,4-dipic complexes to halide ions was found compared to the corresponding pic complexes due to the additional COO− moiety.

Clopamide ((4-chloro-N-2,6-dimethylpiperidin-1-yl)-3-sulfamoylbenzamide, LH) drug is used worldwide in the treatment of hypertension and oedema. Despite its medical application its structure has not yet been published. We report the crystal structure of clopamide anhydrate and hemihydrate and a structural landscape of different polymorphs and solvatomorphs of its copper(II) complexes. Our main challenge was the growth of single crystals for X-ray diffraction experiments and then the analysis of the molecular arrangements of the pure drug as well as the series of complexes organised by the coordination bond and by different secondary interactions. We present how the inclusion of water contributes to the crystal perfection of the drug crystals (1 and 2). The newly defined chalcogen bond is recognised in the clopamide anhydrate crystals being in competition with an intramolecular halogen bond. All Cu(II) complexes have a square-planar coordination geometry, in which copper(II) centres are surrounded by piperidine-N and carbonyl-O donor atoms in a five-membered chelate ring. The two ligands are in trans positions. The solvatomorph crystals, containing small homologous alcohols (3–6), have been found to be isostructural (P) with increasing size of void and unit cell volumes which terminates using n-butanol. In the solvent-free polymorph [CuL2] crystals (7–9), the complex molecules form parallel columns strengthened by N–H⋯O interactions between the ligand sulfonamide groups. The arrangement of these columns in 7 (P) is similar to that of the solvate 3 (P), while 8 (P) transitions to 9 (R), where perfect threefold symmetry is realised, although leaving large empty spaces in the lattice. The columnal arrangement is preserved in the crystal containing dichloromethane (10) but the columns are no longer parallel. The solvate content and thermal behaviour of the crystals were studied by IR and thermoanalytical methods. The solution structure of the [CuL2] complex was investigated in DMSO by EPR spectroscopy at 77 K. These results of the systematic comparison of several polymorphic and solvatomorphic crystal arrangements contribute to the better understanding of the structure-directing effects, which provide strategies to control the molecular self-assembly.

A molecular pre-catalyst complex, [CuII(indH)(OClO3)(NCCH3)](ClO4)·CH3CN (1·CH3CN) with the 3N pincer ligand 1,3-bis(2′-pyridyl)iminoisoindoline (indH) was immobilized on indium tin oxide (ITO) transparent conducting substrate to generate O2 electrocatalytically for over 20 hours at pH 10 in a carbonated buffer, reaching a turnover of 139 with no signs of CuOx/Cu(OH)2 formation at the surface. Further electrolysis experiments revealed that the catalyst was present in the aqueous phase, despite the poor initial solubility of the pre-catalyst (1). In order to identify the actual form responsible for this important catalytic reaction, the aquo complex [CuII(ind)(OClO3)(OH2)]·CH3OH (2·CH3OH) was structurally characterized. Spectroscopic investigations of a solid isolated from the buffer used in the electrolysis reaction and solution equilibrium studies using 2 indicated that the [CuII(ind)(OH)] form occurs at pH 10. Electron paramagnetic resonance (EPR) spectroscopy and DFT calculations confirmed a distorted {3N,O}eq coordination plane in solution, as found in 2. The buffer (i.e. bicarbonate/carbonate) may affect reactivity in two ways: as an external base facilitating the proton-coupled electron transfer steps; and/or displacing the inner-sphere solvent molecules from the favourable quasi-equatorial position, thus inhibiting the catalysis. Structural features of a tri-nuclear cluster [CuII3(ind)3(μ3-CO3)(CH3OH)(OClO3)] (3) isolated under basic conditions confirmed that beside acting as an external base, the inhibiting effect of carbonate anions may also play a role. In acetonitrile-water solutions, where both 1 and 2 exhibit reasonable solubility, experimental findings supported by DFT calculations suggest that it is the ind− ligand which is being oxidized while the cupric ion remains redox-inactive which is very unusual yet of great significance for the creation of a new generation of low-cost Cu-based water oxidation catalysts as well as potentially other 1st row transition metals.

A series of half-sandwich polypyridyl complexes was synthesized and compared focusing on structural, cytotoxic and aqueous solution behaviour. The formula of the synthesized complexes is [M(arene)(N,N)Cl]Cl, where M: Ru or Rh, arene: p-cymene, toluene or C5Me5−, (N,N): 2,2′-bipyridine (bpy), 4,4′-dimethyl-2,2′-bipyridine (dmb), 1,10-phenanthroline (phen) or 2,9-dimethyl-1,10-phenanthroline (neo). The structures of five half-sandwich complexes were determined by X-ray crystallography. It was found that introducing methyl groups next to the coordinating nitrogen atoms of the bidentate ligand causes steric congestion around the metal centre which changes the angle between ligand planes. The ligands and the Rh complexes showed significant cytotoxicity in A2780 and MES-SA cancer cell lines (IC50 = 0.1–56 μM) and in the cisplatin-resistant A2780cis cells. Paradoxically, phen and dmb as well as their half-sandwich Rh complexes showed increased toxicity against multidrug resistant MES-SA/Dx5 cells. In contrast, coordination to Ru caused loss of toxicity. Solution equilibrium constants showed that the studied metal complexes have high stability, and no dissociation was found for Ru and Rh complexes even at micromolar concentrations in a wide pH range. However, in the case of Ru complexes a slow and irreversible decomposition, namely arene loss, was also observed, which was more pronounced in light exposure in aqueous solution. In the case of neo, the methyl groups next to the nitrogen atoms significantly decrease the stability of complexes. For Rh complexes, the order of the stability constants corrected with ligand basicity (log K*): 9.78 (phen) > 9.01 (dmb) > 8.89 (bpy) > 3.93 (neo). The coordinated neo resulted in an enormous decrease in the chloride ion affinity of Ru compounds. Based on the results, a universal model was introduced for the prediction of chloride ion capability of half-sandwich Rh and Ru complexes. It combines the effects of the bidentate ligand and the M(arene) part using only two terms, performing multilinear regression procedure.

Detailed equilibrium, spectroscopic, and SOD activity studies are reported on nickel(II) complexes formed with the N-terminally free HHDLPCGVY-NH2 (NiSODHH) and HCDLPHGVY-NH2 (NiSODHC) peptides mimicking the nickel binding loop in NiSOD. In these model peptides, cysteine was incorporated in different positions in order to gain better insight into the role of the cysteine residues in NiSOD. The results are compared with those obtained with the wild-type fragment of NiSOD. The complex formation equilibria of nickel(II) with the two peptides exhibit different features. In the case of NiSODHH, the ligand field of the (NH2,NIm,NIm,S-) donor set is not strong enough to cause spin pairing and an octahedral paramagnetic complex is formed under physiological conditions. In contrast, NiSODHC forms a square-planar diamagnetic complex with (NH2,N-,S-,NIm) donors which exhibits remarkable SOD activity. Our results unambiguously prove that the presence of cysteine in the secondary position of the peptide chain is crucial to establish the square-planar geometry in the reduced form of NiSOD, while the distant cysteine affects the redox properties of the Ni(II)/Ni(III) couple. Compared to the model systems, the Ni(II) complex with the wild-type fragment of NiSOD exhibits superior SOD activity. This confirms that both cysteinyl residues are essential in the efficient degradation of superoxide ion. The enzyme mimetic complexes are also capable of assisting the decomposition of superoxide ion; however, they show considerably smaller catalytic activity due to the absence of one of the cysteine residues.

Copper(II) complexes of pyridine-based ligands functionalized with alanine (

Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C5Me5) and Ru(η6-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity.

Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η5-C5Me5)(H2O)3]2+ and [Ru(η6-p-cymene)(H2O)3]2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range, no significant dissociation occurs at physiological pH. The hybrids and their Rh(η5-C5Me5) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η5-C5Me5) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells, meanwhile, the Ru(η6-p-cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η5-C5Me5) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding.

Tools to describe isostructurality are important in the understanding of close packing principles and in the fine-tuning of crystal properties. In order to present how different methods work in practice, a series of 2-phenylbenzimidazole derivatives substituted on the phenyl ring in the ortho, meta and para positions or simultaneously in two different positions by F, Cl and Br were selected. The flexibility of the phenylbenzimidazole frame permits a gradual isostructural change of the structures with step-by-step alteration of the internal arrangement as well as of the lengths of the unit cells perpendicular to the determining N–H⋯N hydrogen bonded chains. The exchange of the different halogen substituents alters the angle between the neighbouring benzimidazole moieties and the system of the secondary interactions, and finally the isostructurality is terminated. The series of isostructural crystals look like a lab jack lifted at different heights. Although the neighbouring members of the series are highly similar, the extremes of the list vary deliberately keeping the space group and Z. This raises the question about the extents of structural differences what we still consider isostructural. The preference of certain intermolecular interactions divides the investigated isostructural Pbca crystals into two subgroups like a switch. The definition of isostructurality does not consider supramolecular similarity, although it may have a determining role as shown. It is presented how isostructurality can be described by numerical descriptors. Cell similarity (π), isostructurality (Is), and molecular isometricity indices are calculated. Correlations of the molecular conformation, secondary interactions and the crystallographic parameters are revealed by statistical methods. With the use of these methods, we provide an easy way to recognise and to characterize isostructurality. We show that the prerequisites of isostructurality are the similar composition and conformation of the compounds, with their analogous molecular and supramolecular arrangement in the crystals having the same space group and Z. Exploitation of the Cambridge Structural Database for systematical investigations to complete the isostructural series is essential.

α-N-Heterocyclic thiosemicarbazones are an important class of investigational anticancer drugs. The most prominent representative is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine), which has shown promising results in clinical trials and is currently evaluated in phase III. In this study, we investigated the influence of a chalcogen atom exchange from S (Triapine) to O (O-Triapine) and Se (Se-Triapine) and the methylation of the hydrazonic NH moiety (Me-Triapine) on their complexation with Fe(ii), Fe(iii) and Cu(ii) ions and their cytotoxicity. The main aim of this study was to characterize and compare the most feasible chemical forms in solution, their stability and redox properties, as well as to reveal the relationships of the solution speciation and kinetic data with cytotoxic activity. The complex equilibria and redox properties of the complexes were characterized by the combined use of pH-potentiometry, UV-visible spectrophotometry, electron paramagnetic resonance spectroscopy, and cyclic voltammetry. These revealed that Se-Triapine forms Cu(ii) complexes with higher, and O-Triapine with lower stability as compared with Triapine. Me-Triapine, which is not able to coordinate via the typical (N,N,S-) donor set, nevertheless coordinates to Cu(ii) with unexpected high stability. The Cu(ii) complexes of Se-Triapine and Me-Triapine can be relatively slowly reduced by glutathione at pH 7.4 (but not by ascorbate), similarly to Cu(ii)-Triapine. In contrast, the Cu(ii)-O-Triapine complex can be reduced by both reducing agents in rapid redox reactions. Se-Triapine and Triapine form high stability complexes with both Fe(ii) and Fe(iii) ions, while O-Triapine has a much stronger preference towards Fe(iii) and Me-Triapine towards Fe(ii). This difference in the iron preference of the ligands seems to have a strong impact on their cytotoxic effects, which was measured in a human uterine sarcoma cell line (MES-SA) and its multidrug-resistant subline (MES-SA/Dx5). The Cu(ii) complexes of these calcogensemicarbazones are moderately toxic, and the highest level of ROS generation was found for the Cu(ii) complex of O-Triapine, which is the most reducible.

The terminal N-mono- and dimethylated derivatives of an estrone-salicylaldehyde thiosemicarbazone hybrid and their highly cytotoxic Cu(II) complexes were synthesized and characterized in addition to their structurally related simpler bicyclic analogues. Solution stability and structure of the complexes were determined by UV-visible spectrophotometry and electron paramagnetic resonance spectroscopy. The monomethylation has a minor influence on the pK

One of the main directions of steroid research is the preparation of modified derivatives in which, in addition to changes in physicochemical properties, receptor binding is significantly altered, thus a bioactivity different from that of the parent compound predominates. In the frame of this work, 2-arylidene derivatives were first synthesized by regioselective modification of the A-ring of natural sex hormone, 5α-dihydrotestosterone (DHT). After Claisen-Schmidt condensations of DHT with (hetero)aromatic aldehydes in alkaline EtOH, heterocyclizations of the α,β-enones were performed with 3-amino-1,2,4-triazole, 3-aminopyrazole and 3-amino-5-methylpyrazole in the presence of t-BuOK in DMF to afford 7'-epimeric mixtures of A-ring-fused azolo-dihydropyrimidines, respectively. Depending on the electronic demand of the substituents of the arylidene moiety, spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the heteroring led to triazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines in good yields, while, using the Jones reagent as a strong oxidant, 17-oxidation also occurred. The crystal structures of an arylidene and a triazolopyrimidine product have been determined by single crystal X-ray diffraction and both were found to crystallize in the monoclinic crystal system at P21 space group. Most derivatives were found to diminish the transcriptional activity of androgen receptor (AR) in reporter cell line. The candidate compound (17β-hydroxy-2-(4-chloro)benzylidene-5α-androstan-3-one, 2f) showed to suppress androgen-mediated AR transactivation in a dose-dependent manner. We confirmed the cellular interaction of 2f with AR, described the binding in AR-binding cavity by the flexible docking and showed the ability of the compound to suppress the expression of AR-regulated genes in two prostate cancer cell lines.

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.

The structure-directing effects of four O,O′-donor hy­droxy­pyri­dine­carboxyl­ate derivatives in their com­plexation with ZnII have been investigated by single-crystal X-ray diffraction. One octahedral and two trigonal bipyramidal mononuclear com­plexes, as well as a pyridino­late-bridged dinuclear complex with octahedral geometry, were detected., The coordination properties of four hy­droxy­pyri­dine­carboxyl­ates, designed for the treatment of iron-overloading con­ditions as bidentate O,O′-donor ligands, have been studied with ZnII in the solid state. The coordination com­pounds [Zn(A1)2(H2O)2] (1), [Zn(A2)2(H2O)] (2), [Zn(A3)2(H2O)]·2H2O (3) and [Zn2(B1)4(H2O)2]·4H2O (4), where the ligands are 1-methyl-4-oxidopyridinium-3-­carboxyl­ate (A1, C7H6NO3), 1,6-di­methyl-4-oxidopyridinium-3-carboxyl­ate (A2, C8H8NO3), 1,5-di­methyl-4-oxido-pyridinium-3-carboxyl­ate (A3, C8H8NO3) and 1-methyl-3-oxidopyridinium-4-carboxyl­ate (B1, C7H6NO3), have been synthesized and analysed by single-crystal X-ray diffraction. The ligands were chosen to probe (i) the electronic effects of inverting the positions of the O-atom donor groups (i.e. A1 versus B1) and (ii) the electronic and steric effects of the addition of a second methyl group in different positions on the pyri­dine ring. Two axially coordinated water molecules resulting in a six-coordinated symmetrical octahedron com­plement the bis-ligand com­plex of A1. Ligands A2 and A3 form five-coordinated trigonal bipyramidal com­plexes with one additional water molecule in the coordination sphere, which is a rarely reported geometry for ZnII com­plexes. Ligand B1 shows a dimeric structure, where the two Zn2+ dications have slightly distorted octahedral geometry and the pyridino­late O atom of the neighbouring com­plex bridges them. The coordination spheres of the Zn2+ dications and the supramolecular structures are discussed in detail. The packing arrangements of 1–3 are similar, having alternating hydro­philic and hydro­phobic layers, however the similarity is broken in 4. The obtained coordination geometries are com­pared with their previously determined CuII analogues. The study of the individual com­plexes is com­plemented with a com­prehensive analysis of ZnII com­plexes with oxygen donor ligands with data from the Cambridge Structural Database.

An estrone–salicylaldehyde thiosemicarbazone hybrid (estrone–TSC) containing integrated domains was designed and synthesized with excellent yield via the condensation reaction of thiosemicarbazide and 2-formyl-estrone under optimized microwave reaction conditions. A structurally related bicyclic derivative (thn-TSC) starting from 5, 6, 7, 8-tetrahydro-1-naphtol (th-1-n) was also prepared in addition to their copper(II) complexes. The ligands have somewhat higher pKa values determined for the deprotonation of the hydroxyl group by UV-visible spectrophotometric and fluorometric titrations than the reference compound salicylaldehyde thiosemicarbazone (STSC), and are neutral at physiological pH. The novel conjugates are more lipophilic and possess higher membrane permeability than STSC based on the n-octanol/water partitioning and the parallel artificial membrane permeability assays, respectively. The isolated [Cu(estrone–TSCH−2)] and [Cu(thn-TSCH−2)] complexes were characterized by ESI-MS, UV-visible and EPR spectroscopy and a detailed solution study was performed to reveal their stoichiometry, stability and reduction by glutathione. The crystal structure of the ligand thn-TSC and its complex [Cu(thn-TSCH−1)Cl] was studied by single crystal X-ray diffraction method. The complexes are fairly stable at pH 7.4, the observed stability order is STSC < thn-TSC < estrone–TSC, and are able to oxidize glutathione readily. The novel ligands thn-TSC and estrone–TSC were found to be only moderately cytotoxic against several human cancer cell lines ; however rather low IC50 values were measured in the hormone-responsive MCF-7 breast cancer cell lines (thn-TSC: 3.7 μM, estrone–TSC: 6.4 μM). The copper(II) complexes exhibited high cytotoxicity (IC50 < 0.3–2 μM) and were considerably more cytotoxic than the respective ligands. Low level of reactive oxygen species was measured and a weak GSH depletion was observed for the complexes of thn-TSC and estrone–TSC in SUM159 breast cancer cells, thus their mechanism of action might be related to the induction of oxidative stress.

Detailed equilibrium, spectroscopic and superoxide dismutase (SOD) activity studies are reported on a nickel complex formed with a new metallopeptide bearing two nickel binding loops of NiSOD. The metallopeptide exhibits unique nickel binding ability and the binuclear complex is a major species with 2×(NH2,Namide,S−,S−) donor set even in an equimolar solution of the metal ion and the ligand. Nickel(III) species were generated by oxidizing the NiII complexes with KO2 and the coordination modes were identified by EPR spectroscopy. The binuclear complex formed with the binding motifs exhibits superior SOD activity, in this respect it is an excellent model of the native NiSOD enzyme. A detailed kinetic model is postulated that incorporates spontaneous decomposition of the superoxide ion, the dismutation cycle and fast redox degradation of the binuclear complex. The latter process leads to the elimination of the SOD activity. A unique feature of this system is that the NiIII form of the catalyst rapidly accumulates in the dismutation cycle and simultaneously the NiII form becomes a minor species., Nickel binding complexes: A nickel complex formed with a new metallopeptide bearing twin nickel binding loops of NiSOD exhibits unique nickel binding ability. The binuclear complex is a major species even in an equimolar solution. The complex exhibits superior superoxide dismutase (SOD) activity. A unique feature of this system is that the NiIII form of the catalyst rapidly accumulates in the dismutation cycle and the NiII form simultaneously becomes a minor species.

Compounds containing redox active permanganate anions and complexed silver cations with reducing pyridine ligands are used not only as selective and mild oxidants in organic chemistry but as precursors for nanocatalyst synthesis in low-temperature solid-phase quasi-intramolecular redox reactions. Here we show a novel compound (4Agpy2MnO4·Agpy4MnO4) that has unique structural features including (1) four coordinated and one non-coordinated permanganate anion, (2) κ1O-permanganate coordinated Ag, (3) chain-like [Ag(py)2]+ units, (4) non-coordinated ionic permanganate ions and an [Ag(py)4]+ tetrahedra as well as (5) unsymmetrical hydrogen bonds between pyridine α-CHs and a permanganate oxygen. As a result of the oxidizing permanganate anion and reducing pyridine ligand, a highly exothermic reaction occurs at 85 °C. If the decomposition heat is absorbed by alumina or oxidation-resistant organic solvents (the solvent absorbs the heat to evaporate), the decomposition reaction proceeds smoothly and safely. During heating of the solid material, pyridine is partly oxidized into carbon dioxide and water; the solid phase decomposition end product contains mainly metallic Ag, Mn3O4 and some encapsulated carbon dioxide. Surprisingly, the enigmatic carbon-dioxide is an intercalated gas instead of the expected chemisorbed carbonate form. The title compound is proved to be a mild and efficient oxidant toward benzyl alcohols with an almost quantitative yield of benzaldehydes.

The stoichiometry and thermodynamic stability of vanadium(IV/V) and copper(II) complexes of pyridoxal thiosemicarbazone and pyridoxal-N 3 ,N 3 -dimethylthiosemicarbazone have been determined by pH-potentiometry (V IV O), EPR (V IV O/Cu II ), UV–Vis (Cu II , V IV O and V V ) and 51 V NMR spectroscopy (V V ) in 30% (w/w) dimethyl sulfoxide/water solvent mixture. In all cases, mono-ligand complexes are formed in different protonation states. In addition, the proton-dissociation constants of the ligands were also determined by pH-potentiometry, UV–Vis and 1 H NMR spectroscopy. The solid state structures of the monoprotonated forms (V V O 2 (L 1 H)×1.5H 2 O and V V O 2 (L 2 H)×0.8H 2 O) of the V V complexes were characterized by single-crystal X-ray diffraction analysis. The mono-ligand complexes of Cu II and V V are dominant at physiological pH. With all investigated metal ions the pyridoxal moiety of the ligand causes an extra deprotonation step between pH 4 and 7 due to the non-coordinating pyridine-NH + . The pyridoxal-containing ligands form somewhat more stable complexes with both V IV O and Cu II ions than the reference compound salicylaldehyde thiosemicarbazone. Dimethylation of the terminal amino group resulted in the formation of V V and Cu II complexes with even higher stability.

The effects of methyl substituents at different positions on the 2-formylpyridine thiosemicarbazone (FTSC) core structure on various physico-chemical properties were investigated. Proton dissociation processes, aqueous solution stability, isomer distribution in different solvents, fluorescence properties and lipophilic character of FTSC, pyridine-2-carboxaldehyde N 4 , N 4 -dimethylthiosemicarbazone (PTSC), 2-acetylpyridine thiosemicarbazone (AcFTSC) and 2-acetylpyridine N 4 , N 4 -dimethylthiosemicarbazone (AcPTSC) were studied and compared under the same conditions. There are more and more indications that Cu(II) ions play an important role in the biological activity of anticancer thiosemicarbazones. Therefore, the complex formation equilibria of FTSC with Cu(II) ions were studied by pH-potentiometry, UV–visible spectrophotometry and electron paramagnetic resonance (EPR) spectroscopy to determine stoichiometry, stability constants and solution structures of the complexes formed in aqueous solution (with 30% DMSO). Mono-ligand complexes in different protonation states were identified such as [CuLH] 2+ , [CuL] + and [CuL(OH)] with (N pyridyl ,N,S)(H 2 O), (N pyridyl ,N,S − )(H 2 O) and (N pyridyl ,N,S − )(OH) coordination modes, respectively. At ligand excess two kinds of isomers of a bis complex [CuL 2 ] were detected at pH > 7, in which binding of the ligands via (N pyridyl ,N,S − )(N) and (N pyridyl ,N,S − )(S − ) donor sets is probable at the equatorial positions. Based on the stability data, [CuL] + complexes of the α- N -pyridyl thiosemicarbazones are predominant at pH 7.4 at 1:1 metal-to-ligand ratio possessing such high solution stability that their decomposition is not likely even at biologically relevant micromolar concentrations. In addition, FTSC and all methylated derivatives investigated show similar Cu(II) binding abilities which is in contrast to the respective Fe(II)/(III) complexes where terminal dimethylation distinctly increases the solution stabilities.

Our aim is to combine the preorganized structure of tripodal scaffolds and the advantageous metal-binding ability of histidine subunits. To this end, recently we have studied the copper(II) complexes of the tris(L-histidyl)-functionalized tren derivative, tren3his. Here we report the copper(II)-binding properties of the mono- and bis(L-histidyl)-functionalized tren ligands (tren1his (L1) and tren2his (L2)), and thus explore the impact of increasing histidine ‘density’ on the copper(II) binding of these tripodal peptides. Our solution equilibrium study was supplemented by several (UV-vis, CD, ESR, and NMR) spectroscopic and MS methods. The mono-His derivative L1 forms only mononuclear complexes. Above pH 4, the tren-like subunit is the main binding site, which is supplemented by an imidazole coordination. In the case of L2, both mono- and dinuclear copper(II) species are formed. In the acidic–neutral pH range, the highly stable bis-histamine-type binding mode dominates in the equimolar solution, while at a higher pH amide coordinated complexes are present. The bis-histamine coordination in CuHL2 creates a preorganized structure, which promotes the binding of a second metal at the tren-like binding site with {N−,Ntert,N−} coordination in Cu2H−1L2/Cu2H−2L2. Only the dinuclear Cu2H−2L2 complex was found to efficiently catalyze the oxidation of H2DTBC. The kinetic data resulted in a very high kcat/KM ratio (4360 M−1 s−1), which is due to the exceptionally strong substrate-binding ability of the dinuclear complex. However, the oxidation of the substrate within this adduct, which is a common feature of catalytically active dicopper(II) complexes, does not occur in the absence of dioxygen. This finding implies that the role of dioxygen is the oxidation of the substrate activated by the dinuclear complex. We assume a Cu(II)Cu(II)–catecholate–Cu(II)Cu(I)–semiquinone valence tautomer (VT) equilibrium. The semiquinone formed in small quantities reacts with dioxygen in a rate-determining step, which eventually results in DTBQ and H2O2 products. The Cu(II)–L2 complexes also exhibit efficient superoxide dismutase-like activity, supporting the versatility of tripodal peptide complexes in redox enzyme mimicking.

The polymorphism of a porous, non-covalently bonded ionic organic framework is reported. The framework is constructed by hydrogen bonding and anion⋯π interactions. In a solvatomorphic lattice, pyridine takes part in the framework formation. The role of molecular rigidity in framework construction is proven by analogous non-porous crystals, where polymorphism also appears.

Solution chemical properties of two bidentate pyrazolyl thiosemicarbazones 2-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Me-pyrTSC), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Ph-pyrTSC), stability of their Cu(II) and Ru(η

Compounds containing redox active permanganate anions and complexed silver cations with reducing pyridine ligands are used not only as selective and mild oxidants in organic chemistry but as precursors for nanocatalyst synthesis in low-temperature solid-phase quasi-intramolecular redox reactions. Here we show a novel compound (4Agpy

The solution chemical properties such as proton dissociation, complex formation with copper(II) and gallium(III) ions in addition to antibacterial and antitumor activity of a novel tridentate salicyaldehyde semicarbazone-estrone hybrid (estrone-SC) and a related bicyclic compound (thn-SC) were investigated. The crystal structure of complex [Cu(thn-SCH−1)Cl] was studied by single crystal X-ray diffraction method. Estrone-SC and thn-SC form mono-ligand complexes with Cu(II) characterized by relatively high stability, however, they are much less stable than their thiosemicarbazone analogues. The neutral Cu(II) complexes with (O−,N,O−)(H2O) coordination mode predominate at physiological pH. Estrone-SC and thn-SC are more efficient Ga(III) binders in comparison with thiosemicarbazones, although the complexes also suffer dissociation at pH 7.4. The Cu(II) complex of estrone-SC displayed significant cytotoxicity in A549, SW480 and CH1/PA cancer cells, and moderate apoptosis induction and ROS formation. The semicarbazone compounds did not exhibit antibacterial effect; unlike the related Cu(II)-thiosemicarbazone complexes represented by the fairly low MIC values (3–50 μM) obtained on the Gram-positive Staphylococcus aureus and Enterococcus faecalis bacteria.

Two new tripodal peptides containing non-protected N-terminal (L1, tren3his) and C-terminal (L2, nta3his) histidines have been synthesized in order to combine the structuring effect of tripodal scaffolds and the strong metal binding properties of histidine moieties. In the present work the copper(II) complexes of these ligands have been studied by combined pH-metric, UV-Vis, CD, EPR and MS methods. At a 1 : 1 metal-to-ligand ratio the two ligands behave as the corresponding dipeptides containing N/C-terminal histidines, but above pH 9 the participation of the tertiary amine in the fused chelate rings results in unique binding modes in the case of both ligands. Besides, the formation of oligonuclear complexes also confirms the positive influence of tripodal platforms on metal coordination, and provides the potential to be efficient functional models of oxidase enzymes. Accordingly, the oligonuclear complexes of both ligands exhibit considerable catecholase-like activity. The oxidation of 3,5-di-tert-butyl-catechol proceeds with the participation of separated Cu2+ centers in the presence of L1 complexes. However, the proximity of the two metal ions in the dinuclear complexes of L2 allows their cooperation along the catalytic cycle. Substrate binding modes, effects of reactants, intermediate and side product formation have also been studied, allowing us to propose a plausible catalytic mechanism for each copper(II)–ligand system.

Copper(II) complexes of a new polydentate tripodal ligand trenpyz (L, tris[2-(5-pyrazolylmethyl)aminoethyl]amine) were characterized in both solution and solid states. A combined evaluation of potentiometric UV-Vis and EPR data provided both thermodynamic and structural information on the complexes formed in solution. In equimolar solution the highly stable square pyramidal CuHL and trigonal bipyramidal CuL are the dominant species at around pH 3 and 5–8, respectively. Above pH 8 further deprotonation was observed (pK = 9.56), which is related to the formation of a copper(II)-bound pyrazolate anion. This creates the possibility for the formation of oligonuclear complexes, through pyrazolate bridges, and at a 3/2 Cu(II)/L ratio three trinuclear complexes were identified, similar to the copper(II)–tachpyz (N,N′,N′′-tris(5-pyrazolylmethyl)-1,3,5-cis,cis-triamino-cyclohexane) system studied earlier. The trinuclear complexes of the two ligands have considerably different speciations, due to the different denticities of tripodal platforms. At the optimal pH the catechol oxidase activities of the triply deprotonated trinuclear complexes of trenpyz and tachpyz are similar, but the pH-rate constant profiles are significantly different, as a consequence of the deviations in their speciation. Consequently, the H2dtbc oxidation promoted by these trinuclear complexes can be easily controlled by the denticity of the tripodal ligands, since it affects the coordination environment of the central metal ion, which is proposed to be the main actor during the reaction.

Complex formation processes of [Ru(η6-p-cymene)(H2O)3]+ and [Rh(η5-C5Me5)(H2O)3]+ organometallic cations with 8-hydroxyquinoline (HQ) ligands were studied in aqueous solution by the combined use of 1H NMR spectroscopy, UV-visible spectrophotometry and pH-potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with the in vitro cytotoxicity against a pair of cancer cell lines, responsive and resistant to classic chemotherapy. The solid phase structure of the [Rh(η5-C5Me5)(8-quinolinolato)(Cl)] complex was characterized by single-crystal X-ray diffraction analysis. In addition to the unsubstituted HQ its 7-(1-piperidinylmethyl) (PHQ) and 5-sulfonate (HQS) derivatives were involved. PHQ has a significant preference for targeting multidrug resistant cancer cell lines, while HQS served as a water soluble model compound. The equilibrium studies revealed the formation of mono[M(L)(H2O)] complexes with prominently high solution stability, which predominate at physiological pH even in the micromolar concentration range, and the formation of mixed hydroxido [M(L)(OH)] complexes was characterized by relatively high pKa values (8.5–10.3). In comparison to the Rh(η5-C5Me5) species the complexation process with Ru(η6-p-cymene) is much slower, and both the pKa values and the H2O/Cl− co-ligand exchange constants are lower by 1–1.5 orders of magnitude. The stability order obtained for these organometallic complexes is as follows: HQS > HQ > PHQ. The cytotoxicity of the ligands and their Ru(η6-p-cymene) and Rh(η5-C5Me5) complexes was investigated against MES-SA (human uterine sarcoma) cell line and its multidrug resistant counterpart (MES-SA/Dx5). HQ and its complexes show similar cytotoxicity in both cell lines. In contrast, PHQ and its Rh(η5-C5Me5) complex are more potent against MES-SA/Dx5 cells, while this selectivity could not be observed for the Ru(η6-p-cymene) complex.

The investigation of the linkage isomers of biologically essential and kinetically labile metal complexes in aqueous solutions poses a challenge, as these microspecies cannot be separately studied. Therefore, derivatives are commonly used to initially determine the stability or spectral characteristics of at least one of the isomers. Here we directly detect the isomers, describe the metal ion coordination sphere, speciation and thermodynamic parameters by a synergistic application of temperature dependent EPR and CD spectroscopic measurements in copper(II)-dipeptide systems including His-Gly and His-Ala ligands. The Delta H = (-23 +/- 4) kJ mol(-1) value of the standard enthalpy change corresponding to the peptide-type to histamine-type isomerisation equilibrium of the [CuL](+) complex was corroborated by several techniques. The preferential coordination of the side-chains was observed at lower temperatures, whereas, metal-binding of the backbone atoms became favourable upon increasing temperature. This study exemplifies the necessity of using temperature dependent multiple methodologies for a reliable description of similar systems for upstream applications.

Development of direct late-stage installation of alkyl groups into aromatic systems is an important and challenging task of current organic chemistry. In spite of the existing functionalization methods in organic chemistry for the substitution reactions on aromatic systems, the direct alkylation of aromatic ureas is unknown. Herein, as a first example we report a novel palladium catalyzed fluoroalkylation process by C−H activation for the access of ortho trifluoroethylated aromatic ureas. The application of novel, highly active trifluoroethyl(mesityl)iodonium salt enables the efficient introduction of the trifluoroethyl group at 25 °C in 3 hours in high yields (up to 95%) with good functional group tolerance. DFT calculations have revealed a rate determining oxidative alkyl-group transfer preceded by an unexpected C−H activation route on the Pd center during the catalytic cycle, where the deprotonation is assisted by an external triflate anion.

During the lead-oriented synthesis of new heterocycles, ethyl 4-(cyanomethyl)-5-phenylisoxazole-3-carboxylate was identified as a key intermediate towards the synthesis of new isoxazolo[3,4-c]pyridine scaffolds. The key reaction was the catalytic hydrogenation of ethyl 4-(cyanomethyl)-5-phenylisoxazole-3-carboxylate using Raney/Ni followed by a selective ring closure reaction to afford 3-phenylisoxazolo[3,4-c]pyridin-7(6H)-one and its unsaturated analogue as new ring systems with lead-like properties.

In the crystal, enanti­omerically pure (S)-3-(2-meth­oxy­pheno­thia­zin-10-yl)-N,N,2-tri­methyl­propanaminium hydrogen maleate, also known as levomepromazine maleate, forms a three-dimensional supra­molecular network through N—H⋯O, C—H⋯O and C—H⋯π inter­actions. The asymmetric unit comprises two slightly conformationally different levomepromazine cations and two hydrogen maleate anions., The asymmetric unit of the title salt, C19H25N2OS+·C4H3O4 − [systematic name: (S)-3-(2-meth­oxy­pheno­thia­zin-10-yl)-N,N,2-tri­methyl­propanaminium hydrogen maleate], comprises two (S)-levomepromazine cations and two hydrogen maleate anions. The conformations of the two cations are similar. The major difference relates to the orientation of the meth­oxy substituent at the pheno­thia­zine ring system. The crystal components form a three-dimensional supra­molecular network via N—H⋯O, C—H⋯O and C—H⋯π inter­actions. A comparison of the conformations of the levomepromazine cations with those of the neutral mol­ecule and similar protonated mol­ecules reveals significant conformational flexibility of the pheno­thia­zine ring system and the substituent at the pheno­thia­zine N atom.

The intricate and multifactorial nature of Alzheimer's disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid beta (Aβ) peptide and metal dyshomeostasis. In order to continue the search for new anti-AD drugs, a design strategy was once more followed based on repositioning donepezil (DNP) drug, by ortho-attaching a benzylpiperidine mimetic of DNP moiety to a hydroxyphenyl-benzimidazole (BIM) chelating unit (compound 1). Herein, compound 1 and a positional isomer 2 are compared in terms of their potential multiple properties: both present good acetylcholinesterase (AChE) inhibition (low μmolar range) and are moderate/good inhibitors of Aβ self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the β-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu2+ and Zn2+ (pCu = 14.3, pZn = 6.4, pH 7.4, CL/CM = 10, CM = 10−6 M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Aβ-induced cell toxicity.