Polyaza crown ether as non-nucleosidic building blocks in DNA-conjugates

The synthesis of amphiphilic polyaza crown ether monomers X (palmityl-substituted), Y (cholesteryl-substituted) and Z (dipalmityl-subtituted) and their incorporation into oligonucleotides are described. Their effects on thermal duplex stability were investigated by UV melting curve analysis. Thermal denaturation experiments showed remarkable stabilization of dsDNA by polyaza crown ether monomers when incorporated in opposite positions. The series of polyaza crown ether monomers (X, Y, and Z) with different lipophilicity showed a trend of increased stability of the corresponding dsDNA with increasing lipophilicity of the polyaza crown ether monomer.     

Functionalisation of silica gel with cyclic and acyclic Schiff bases and related d- and/or f-metal complexes

Two different synthetic pathways were devised in order to graft on silica gel organic moieties, containing macroacyclic or macrocyclic compartimental ligands, formed of an inner N₃O₂ or N₂O₂ Schiff base site, able to coordinate d metal ions, and one adjacent O₂O₂ or O₂O₄ crown ether-like chamber suitable for hosting f ions, in the terminal part. These materials can bind d metal ions into the amine-imine moiety. Their subsequent reaction with varying amounts of gadolinium(III) invariantly gives a system in which two grafted copper complexes coordinate only one gadolinium(III) ion with their oxygen-containing chambers, giving rise to a trinuclear Cu₂Gd entity.According to a third strategy, some mono- and heterobi-metallic macrocyclic complexes were transferred from a water/methanol solution into functionalised silica platforms by coordinating their metal ions to the donor group of one silica-anchored organic residual. UV-Vis spectra of solutions containing these metal complexes gave a clear indication of the selective coordinating ability of the donor group towards 3d or 4f metal ions.     

Efficiency,thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review

Gadolinium-based contrast agents are widely used to enhance image contrast in magnetic resonance imaging (MRI) procedures. Over recent years, there has been a renewed interest in the physicochemical properties of gadolinium chelates used as contrast agents for MRI procedures, as it has been suggested that dechelation of these molecules could be involved in the mechanism of a recently described disease, namely nephrogenic systemic fibrosis (NSF). The aim of this paper is to discuss the structure-physicochemical properties relationships of marketed gadolinium chelates in regards to their biological consequences. Marketed gadolinium chelates can be classified according to key molecular design parameters: (a) nature of the chelating moiety: macrocyclic molecules in which Gd3+ is caged in the pre-organized cavity of the ligand, or linear open-chain molecules, (b) ionicity: the ionicity of the complex varies from neutral to tri-anionic agents, and (c) the presence or absence of an aromatic lipophilic residue responsible for protein binding. All these molecular characteristics have a profound impact on the physicochemical characteristics of the pharmaceutical solution such as osmolality, viscosity but also on their efficiency in relaxing water protons (relaxivity) and their biodistribution. These key molecular parameters can also explain why gadolinium chelates differ in terms of their thermodynamic stability constants and kinetic stability, as demonstrated by numerous in vitro and in vivo studies, resulting in various formulations of pharmaceutical solutions of marketed contrast agents. The concept of kinetic and thermodynamic stability is critically discussed as it remains a somewhat controversial topic, especially in predicting the amount of free gadolinium which may result from dechelation of chelates in physiological or pathological situations. A high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) will minimize the amount of free gadolinium released in tissue parenchymas.     

The synthesis of macrocyclic lanthanide complexes derived from 2,5-furandialdehyde and α,ω-alkanediamines

The synthesis of macrocyclic lanthanide complexes via the reaction of 2,5-furandialdehyde with 1,2-diaminoethane, 1,2-diaminopropane and 1,3-diaminopropane in the presence of lanthanide nitrates as templating agents is described. The potential application of the complexes in transmetallation reactions is discussed.     

Monometallic complexes of 1,4,7,10-tetraazacyclododecane containing an imidazolium side: synthesis, characterization, and their interaction with plasmid DNA

The synthesis of macrocyclic polyamine monometallic complexes containing imidazolium salt groups was reported. Their interaction with pUC19 plasmid DNA was studied. The result showed that these complexes can catalyze the DNA cleavage with unprecedented reactivity under physiological conditions.     

Lanthanide complexes of some macrocyclic schiff bases derived from pyridine-2,6-dicarboxaldehyde α,ω-primary diamines

The synthesis of macrocyclic lanthanide complexes via the reaction of pyridine-2,6-dicarboxaldehyde with 1,2-diaminoethane, 1,2-diaminopropane and 1,3-diaminopropane in the presence of lanthanide nitrates as templating agents is discussed together with the use of the lanthanum derivatives in transmetallation reactions with copper(II).     

Antiamyloid properties of fullerene C60 derivatives

A comparative estimation of the ability of complexes of fullerene C60 with polyvinylpyrrolidone and fullerene C60 derivatives (the sodium salt of the polycarboxylic derivative of fullerene C60, sodium fullerenolate), has been carried out. The fullerenes destroyed amyloid fibrils of the Abeta(1-42) peptide of the brain and the muscle X-protein. A study of the effect of fullerenes on muscle actin showed that complexes of fullerene C60 with polyvinylpyrrolidone and sodium fullerenolate did not prevent the filament formation of actin, nor did they destroy its filaments in vitro. Conversely, sodium salt of the polycarboxylic derivative of fullerene C60 destroyed actin filaments and prevented their formation. It was concluded that sodium fullerenolate and complexes of fullerene C60 with polyvinylpyrrolidone are the most effective antiamyloid compounds among the fullerenes examined.     

Ternary Gd(III)L-HSA adducts: evidence for the replacement of inner-sphere water molecules by coordinating groups of the protein. Implications for the design of contrast agents for MRI

Two novel gadolinium(III) chelates based on the structure of the heptadentate macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) ligand have been synthesized and their relaxometric and luminescent properties thoroughly investigated. They contain two water molecules in the inner coordination sphere in fast exchange with the bulk solvent and bear either a p-bromobenzyl or a p-phosphonatomethylbenzanilido substituent for promoting further interaction with macromolecular substrates. Upon interaction with human serum albumin the expected relaxation enhancement is not observed owing to displacement of the two inner-sphere water molecules of the complexes by a donor atom (likely from a carboxylate group) on the protein and possibly the phosphate anion of the buffered solution, respectively. We modeled the observed behavior by measuring the decrease of the relaxation rate of the water protons upon addition of malonate anion to aqueous solutions of the complexes. Conversely, no change in the hydratation state of the Gd(III) center for both complexes has been observed when the substrate for the formation of the macromolecular adduct is represented by poly-beta-cyclodextrin.     

Advances in asymmetric oxidative kinetic resolution of racemic secondary alcohols catalyzed by chiral Mn(III) salen complexes

Enantiomerically pure secondary alcohols are essential compounds in organic synthesis and are used as chiral auxiliaries and synthetic intermediates in the pharmaceutical, agrochemical, and fine chemical industries. One of the attractive and practical approaches to achieving optically pure secondary alcohols is oxidative kinetic resolution of racemic secondary alcohols using chiral Mn(III) salen complexes. In the last decade, several chiral Mn(III) salen complexes have been reported with excellent enantioselectivity and activity in the homogeneous and heterogeneous catalysis of the oxidative kinetic resolution of racemic secondary alcohols. This review article is an overview of the literature on the recent development of chiral Mn(III) salen complexes for oxidative kinetic resolution of racemic secondary alcohols. The catalytic activity of monomeric, dimeric, macrocyclic, polymeric, and silica/resin supported chiral Mn(III) salen complexes is discussed in detail.     

Actinoplanic acids A and B as novel inhibitors of farnesyl-protein transferase

Actinoplanic acids A and B are macrocyclic polycarboxylic acids that are potent reversible inhibitors of farnesyl-protein transferase. Actinoplanic acids A and B were isolated from Actinoplanes sp. MA 7066 while actinoplanic acid B was isolated from both MA 7066 and Streptomyces sp. MA 7099. Actinoplanic acids A and B are competitive with respect to farnesyl diphosphate and are selective inhibitors of farnesyl-protein transferase because they do not inhibit geranylgeranyl-protein transferase type 1 or squalene synthase. MA 7066 is believed to be a novel species of actinomycetes while MA 7099 is believed to be a novel strain of Streptomyces violaceusniger on the basis of morphological, biochemical and chemotaxonomic characteristics as well as its production of actinoplanic acids.     

Template synthesis, characterization and crystal structure of heptaazadentate Schiff base lanthanide aminopodates

The Schiff base condensation reactions between 2,6-diacetylpyridine and diethylenetriamine in the presence of lanthanum(III) and praseodymium(III) ions as template agents yield, exclusively, heptaazadentate complexes of a podate type with two terminal amine groups, irrespective of the molar ratio of the starting materials used in the synthesis. These complexes, which might be regarded as possible intermediates in the template synthesis of macrocyclic compounds, appear to be the final products. The ring-closure of the partial Schiff base condensation products does not occur either by the transamination mechanism or by the 2,6-diacetylpyridine addition. The rare heptaazadentate behavior of the Schiff base aminopodand in lanthanide complexes is proved by single-crystal X-ray diffraction analysis correlated with spectroscopic characterization. All the seven potential nitrogen donor atoms are available for coordination to the metal ions. The high coordination number of eleven is achieved by the incorporation of two bidentate nitrate anions in the lanthanide coordination sphere.     

Activity of Zn and Mg phthalocyanines and porphyrazines in amyloid aggregation of insulin

Formation of the deposits of protein aggregates—amyloid fibrils in an intracellular and intercellular space—is common to a large group of amyloid‐associated disorders. Among the approaches to develop of therapy of such disorders is the use of agents preventing protein fibrillization. Polyaromatic complexes—porphyrins and phthalocyanines—are known as compounds possessing anti‐fibrillogenic activity. Here, we explore the impact of related macrocyclic complexes—phthalocyanines (Pc) and octaphenyl porphyrazines (Pz) of Mg and Zn—on aggregation of amyloidogenic protein insulin. Pz complexes are firstly reported as compounds able to affect protein fibrillization. The effect of Pc and Pz complexes on the kinetics and intensity of insulin aggregation was studied by the fluorescent assay using amyloid sensitive cyanine dye. This has shown the impact of metal ion on the anti‐fibrillogenic properties of macrocyclic complexes—the effect on the fibrillization kinetics of Mg‐containing compounds is much more pronounced comparing to that of Zn analogues. Scanning electron microscopy experiments have demonstrated that filamentous fibrils are the main product of aggregation both for free insulin and in the presence of macrocyclic complexes. However, those fibrils are distinct by their length and proneness to lateral aggregation. The Pc complexes cause the increase in variation of fibrils length 0.9 to 2.7 nm in opposite to 1.4 to 2.0 nm for free insulin, whereas Pz complexes cause certain shortening of the fibrils to 0.8 to 1.6 nm. The averaged size of the fibrils population was estimated by dynamic light scattering; it correlates with the size of single fibrils detected by scanning electron microscopy.     

The inhibitory effects of 21 mimics of superoxide dismutase on luminol-mediated chemiluminescence emitted from PMA-stimulated polymorphonuclear leukocyte.

Four groups comprising 21 superoxide dismutase (SOD) mimics synthesized by us were comparatively studied for their inhibitory effects on luminol-mediated chemiluminescence emitted from phorbol myristate acetate (PMA)-stimulated polymorphonuclear leukocyte (PMNL). Among these groups, 20-membered macrocyclic bicopper(II) complexes and 13-membered macrocyclic dioxotetramine copper(II) complexes exhibited relatively higher activities of scavenging reactive oxygen species (ROS) produced by PMA-stimulated PMNL as compared with polyamine Cu(II)-Zn(II) complexes and copper(II) complexes of bis-shiff-base. Moreover, distinctly different effects of SOD mimics in the biological system have been found even in the same group. It is suggested that the biological effects of some SOD mimics are related to their structures.     

Antiamyloid properties of fullerene C<Subscript>60</Subscript> derivatives

A comparative estimation of the ability of complexes of fullerene C₆₀ with polyvinylpyrrolidone and fullerene C₆₀ derivatives (the sodium salt of the polycarboxylic derivative of fullerene C₆₀, sodium fullerenolate), has been carried out. The fullerenes destroyed amyloid fibrils of the Aβ(1–42) peptide of the brain and the muscle X-protein. A study of the effect of fullerenes on muscle actin showed that complexes of fullerene C₆₀ with polyvinylpyrrolidone and sodium fullerenolate did not prevent the filament formation of actin, nor did they destroy its filaments in vitro. Conversely, sodium salt of the polycarboxylic derivative of fullerene C₆₀ destroyed actin filaments and prevented their formation. It was concluded that sodium fullerenolate and complexes of fullerene C₆₀ with polyvinylpyrrolidone are the most effective antiamyloid compounds among the fullerenes examined.     

Lanthanide octaethylprophyrins: preparation, association, and interaction with axial ligands

The synthesis of virtually all the lanthanide octaethylporphyrin complexes have been achieved by heating appropriate anhydrous lanthanide halide and octaethylporphyrin in imidazole melt at 210 degrees C for two hours. The lighter lanthanide porphyrin complexes are very susceptible to hydrolysis, the middle lanthanide porphyrin complexes are moderately stable, and the heavier lanthanide porphyrin complexes are relatively more stable to hydrolysis. Two out of four lanthanide porphyrin complexes studied in detail, namely ytterbium and lutetium octaethylporphyrins, aggregate in benzene and the Soret bands in their absorption spectra are about 6 nm shifted to higher energies upon a hundred-fold increase in their concentrations. The aggregations of these lanthanide porphyrin complexes in non-coordinating solvents have been further verified by 1H NMR spectral studies. This spectral behavior can be interpreted qualitatively in terms of the model of the molecular exciton interactions with stacking of at least two prophyrins. A dimeric structure of these lanthanide porphyrin complexes has been proposed on the basis of geometrical considerations. On the contrary, the europium and gadolinium octaethylporphyrins associate very weakly in benzene in the concentration range studied. All four lanthanide porphyrin complexes interact with pyridine and piperidine, and the Soret bands in their absorption spectra are about 8 nm shifted to low energies as compared with their values in pure benzene.     

Macrocyclic copper(II) complexes: superoxide scavenging activity, structural studies and cytotoxicity evaluation

Synthetic superoxide dismutase mimetics have emerged as a potential novel class of drugs for the treatment of oxidative stress related diseases. Among these agents, metal complexes with macrocyclic ligands constitute an important group. In this work we synthesized five macrocyclic copper(II) complexes and evaluated their ability to scavenge the superoxide anions generated by the xanthine-xanthine oxidase system. Two different endpoints were used, the nitro blue tetrazolium (NBT) reduction assay (colorimetric method) and the dihydroethidium (DHE) oxidation assay (fluorimetric method). IC(50) values in the low micromolar range were found in four out of five macrocyclic complexes studied, demonstrating their effective ability to scavenge the superoxide anion. The IC(50) values obtained with the NBT assay for the macrocyclic copper(II) complexes, were consistently higher, approximately threefold, than those obtained with the DHE assay. Spectroscopic and electrochemical studies were performed in order to correlate the structural features of the complexes with their superoxide scavenger activity. Cytotoxicity assays were also performed using the MTT method in V79 mammalian cells and we found that the complexes, in the range of concentrations tested in the superoxide scavenging assays were not considerably toxic. In summary, some of the presented macrocyclic copper(II) complexes, specially those with a high stability constant and low IC(50), appear to be promising superoxide scavenger agents, and should be considered for further biological assays.     

Antifertility,antibacterial, antifungal and percent disease incidence aspects of macrocyclic complexes of manganese(II)

Macrocyclic complexes of Mn(II) were synthesized by template condensation using 2,6-diaminopyridine and diethylenetriamine with malonic, succinic, glutaric and adipic acids. The reaction proceeded smoothly to completion. These 16- to 24-membered N(6), but behaving as tetradentate, macrocyclic complexes were characterized by elemental analyses, molecular weight determinations, infrared, electronic, mass and X-ray spectral analyses. The elemental analyses are consistent with the formation of complexes [Mn(N(6)L(n))Cl(2)]. All the complexes are stable and monomeric in nature, as indicated by the molecular weight determinations. The spectral studies confirmed the proposed framework of the new macrocyclic complexes and indicated an octahedral geometry around the central metal atom. The complexes were screened in vitro against a number of pathogenic fungi and bacteria to assess their growth-inhibiting potential. The testicular sperm density, sperm morphology, sperm motility, density of cauda epididymis, spermatozoa and fertility in mating trials and the biochemical parameters of the reproductive organs of the rat were examined and are discussed.     

Oligonucleotide conjugates of Eu(III) tetraazamacrocycles with pendent alcohol and amide groups promote sequence-specific RNA cleavage

Eu(III) complexes of two neutral bifunctional tetraaaza macrocyclic ligands {1-[1-carboxamido-3-(4-nitrophenyl)propyl]-4,7,10-tris(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane and 2-(4-nitrobenzyl)-1,4,7,10-tetrakis(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane} are prepared. Eu(III) complexes of the isothiocyanate derivatives of these macrocycles are treated with oligonucleotides containing 2′-O-propylamine linkers to form conjugates. Hydrolytic cleavage of an oligoribonucleotide is promoted by Eu(III) macrocyclic oligonucleotide conjugates containing complementary (antisense) sequences. Cleavage is not observed in the presence of Eu(III) conjugates containing scrambled sequences nor by free complex. Despite the fact that one of the free macrocyclic complexes is more reactive than the other, the extent of cleavage observed is similar for conjugates containing either Eu(III) macrocyclic complex.     

Ethanol catalyzed synthesis of titanocene aryl carboxylate complexes and crystal structure of (η-C5H5)2Ti(2-OH-5-S-O2CC6H3)2

A method for the synthesis of titanocene (IV) aryl carboxylate complexes is presented in this paper. It is based on the fact that alcohol can catalyze the reaction between Cp₂TiCl₂ and aryl carboxylate ligands in the presence of sodium hydroxide (NaOH). The effects of the catalyst on the reaction system were studied and the possible reaction mechanism was proposed. This method was used to prepare a series of titanocene (IV) aryl carboxylate complexes and a macrocyclic titanocene (5,5′-dithiodisalicylato titanocene), whose structure was determined by X-ray diffraction analysis.     

Studies on the structure and properties of nickel complexes in a set of amide-based 13-membered macrocyclic ligands

This work reports a systematic investigation to understand the structural, spectroscopic and redox properties of Ni(II) ion in a set of 13-membered amide-based macrocyclic ligands. Four macrocyclic ligands containing e⁻-donating/withdrawing substituents and their Ni(II) complexes have been synthesized and characterized. Structural analysis shows that the macrocyclic ligands create a square-planar environment and nicely accommodate the Ni(II) ion. Electrochemical results suggest that the complexes are capable of undergoing metal-centered oxidation. The electron-donating substituents on ligand lowers the redox potentials and better stabilizes the +3 oxidation state of metal. The electrochemically generated Ni^III species are shown to have rich spectroscopic features. For majority of complexes, the oxidized species are concluded to be Ni^III by their anisotropic EPR spectra typical for Ni^III ion in square-planar geometry. The absorption and EPR spectra for nickel complex bearing an -OMe group on the ligand; however, suggest a Ni(II) complex with a ligand-based radical.