Selenosteroids - promising hybrid compounds with pleiotropic biological activity: synthesis and biological aspects.

It is established that steroid based agents are an example of compounds obtained from natural patterns and are of great importance due to their application in the prevention and treatment of diseases. Selenosteroids are hybrids formed by attaching Se-moiety to a steroid molecule. In these types of hybrids, selenium can be present as selenide or as a part of selenosemicarbazones, isoselenocyanates, selenourea, etc. Attaching a Se-moiety to a biologically active steroid might enhance the biological properties of both fragments. Available literature indicates that these kinds of hybrids demonstrate significant anticancer activity, which renders them interesting in terms of medical use. In this review, we present various methods of synthesis and demonstrate that seleno-steroid compounds are promising molecules for further pharmaceutical application.

Benzimidazole- and Imidazole-Fused Selenazolium and Selenazinium Selenocyanates: Ionic Organoselenium Compounds with Efficient Peroxide Scavenging Activities.

Three new classes of ionic organoselenium compounds containing cationic benzimidazolium and imidazolium ring systems with selenocyanates as counterions are described. The cyclization of N,N'-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)2-Br and N-(CH2)3-Br groups in the presence of potassium selenocyanate (KSeCN) led to formation of the corresponding selenazolium selenocyanates (21a, 21b, 22a, and 22b) and selenazinium selenocyanates (21c, 21d, 22c, and 22d). However, the open-chain selenocyanates with additional selenocyanate counterions (21e, 21f, 22e, and 22f) were formed from the N,N'-disubstituted benzimidazolium and imidazolium bromides having N-(CH2)6-Br groups. Mechanistic studies were carried out to understand the feasibility of such cyclization processes in the presence of KSeCN. The compounds were studied further for their potencies to catalytically reduce H2O2 in the presence of thiols. Interestingly, the cyclic selenazolium (21a, 21b, 22a, and 22b) and selenazinium compounds (21c, 21d, 22c, and 22d) exhibited significantly higher antioxidant activities than the corresponding acyclic selenocyanates (21f, 22e, and 22f). Selected compounds (22d and 22e) were further evaluated for their potencies in modulating the intracellular level of reactive oxygen species (ROS) in a representative macrophage cell line (RAW 264.7). Owing to the cationic nature of compounds, they may target and scavenge mitochondrial ROS in the cellular medium.

Synthesis of Novel Selenocyanates and Evaluation of Their Effect in Cultured Mouse Neurons Submitted to Oxidative Stress.

Herein, we report the synthesis of novel selenocyanates and assessment of their effect on the oxidative challenge elicited by hydrogen peroxide (H2O2) in cultured mouse neurons. First, α-methylene-ß-hydroxy esters were prepared as precursors of allylic bromides. A reaction involving the generated bromides and sodium selenocyanate was conducted to produce the desired selenocyanates (3a-f). We next prepared cultures of neurons from 7-day-old mice (n = 36). H2O2 (10-5 M) was added into the culture flasks as an oxidative stress inducer, alone or combined with one of each designed compounds. (PhSe)2 was used as a positive control. It was carried out assessment of lipid (thiobarbituric acid reactive species, 4-hydroxy-2'-nonenal, 8-isoprostane), DNA (8-hydroxy-2'-deoxyguanosine), and protein (carbonyl) modification parameters. Finally, catalase and superoxide dismutase activities were also evaluated. Among the compounds, 3b, 3d, and 3f exhibited the most pronounced pattern of antioxidant activity, similar to (PhSe)2. These novel aromatic selenocyanates could be promising to be tried in most sophisticated in vitro studies or even at the preclinical level.

Synthesis, characterization and anticancer activity in vitro evaluation of novel dicyanoaurate (I)-based complexes.

Molecular structures containing gold, such as auranofin, have been extensively studied in the diagnosis and treatment of many diseases, including cancer treatment. The pharmacological properties of the newly synthesized unique gold-ligand structures have been reported for different cancer cell lines. However, findings on bishydeten-metal salt complexes with gold are rare. In this work, the synthesis of five novel cyanide-bridged coordination compounds having the closed formulae [Ni(bishydeten)][Au(CN)2]2 (1), [Cu(bishydeten)][Au(CN)2]2 (2), [Zn(bishydeten)2Au3(CN)4][Au2(CN)3] (3), [Cd(bishydeten)0,5]2[Au(CN)2]4.2H2O (4), and [Cd(bishydeten)2][Au(CN)2]2 (5) (where bisyhdeten = N,N-bis(2-hydroxyethyl)ethylene diamine), and their characterization by elemental, infrared, ESI-MS, X-ray (for 2) and thermic measurement methods were performed. Complexes 1 and 3 are thermally more stable than the other three complexes. For these, pharmacological adequacies were also tested. The nucleic acid and protein binding affinities of the Au (I) compounds were also estimated by spectroscopic and electrophoretic techniques. Au (I) complexes were identified as strong chemotherapeutic with mild cytotoxicity, and they demonstrated a dose-dependent inhibition on the growth of cancer cells with IC50 at 0.11 to 0.47 µM. Investigation of mechanisms of action on cells revealed that Au (I) compounds managed to inhibit cell migration and led to a decrease in cytoskeletal proteins such as CK7 and CK20. However, Au (I) compounds failed to inhibit DNA topoisomerase I. Overall, and we suggest that potent antiproliferative activity, mild cytotoxicity, good solubility, and micromolar dosage of Au (I) compounds containing bisyhdeten-metal derivatives render them the potential focus of further studies as chemotherapeutic agents.

Synthesis and Potential Anticancer Activity of Some Novel Selenocyanates and Diselenides.

In the present study, twenty-four selenocyanate and diselenide compounds were synthesized and characterized, and their anticancer activities against the human cancer cell lines Caco2, BGC-823, MCF-7 and PC-3 were determined. Interestingly, most of the new compounds were active in reducing the viability of different cancer cell lines. Two compounds exhibited higher promising activities than other derivatives. The most active compound showed the least IC50 values against the four cancer cell lines, particularly to PC-3 with IC50 values below 5 µm. Two compounds were selected to monitor the expression levels of Bcl-2, IL-2 and caspase-3 molecular biomarkers. Interestingly, the two compounds downregulated the Bcl-2 expression levels and upregulated the expression of IL-2 and caspase-3 in PC-3 cells compared to untreated cells. Moreover, most of the synthesized organoselenides exhibited good Gpx-like activities comparable to ebselen. These results appear that introduction of selenocyanate (-SeCN) or diselenides (-Se-Se-) moiety to some carboxy derivatives could serve as a promising launch point for the further design of this type of organic selenium anticancer agent.

An alternative and simple synthesis of [14 C]potassium cyanate.

The one-step synthesis of [14 C]potassium cyanate from [14 C]urea is described with product characterization by gravimetric specific activity as well as a novel TLC system. The storage, stability, and repurification of [14 C]potassium cyanate are also discussed.

Synthesis of Cyanate Esters Based on Mono-O-Methylated Bisphenols with Sulfur-Containing Bridges.

We described a synthetic approach to bisphenol-based monocyanate esters based on mono-O-methylation of parental bisphenols followed by cyanation of the residual phenolic hydroxyl. Structures of the synthesized compounds were determined by the application of IR, NMR ¹H and 13C spectroscopies, EI and MALDI mass spectrometry, and purity of the final product was controlled by HPLC. We showed that stability of the cyanate esters depends on the nature of the bridging group. Temperature range of thermally initiated cyclotrimerization of synthesized monocyanate ester, as well as reaction enthalpy, was determined by differential scanning calorimetry (DSC).

Electrochemical Aminoxyl-Mediated α-Cyanation of Secondary Piperidines for Pharmaceutical Building Block Diversification.

Secondary piperidines are ideal pharmaceutical building blocks owing to the prevalence of piperidines in commercial drugs. Here, we report an electrochemical method for cyanation of the heterocycle adjacent to nitrogen without requiring protection or substitution of the N-H bond. The reaction utilizes ABNO (9-azabicyclononane N-oxyl) as a catalytic mediator. Electrochemical oxidation of ABNO generates the corresponding oxoammonium species, which promotes dehydrogenation of the 2° piperidine to the cyclic imine, followed by addition of cyanide. The low-potential, mediated electrolysis process is compatible with a wide range of heterocyclic and oxidatively sensitive substituents on the piperidine ring and enables synthesis of unnatural amino acids.

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents.

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 µM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3'-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design.

Organoselenocyanates and symmetrical diselenides redox modulators: Design, synthesis and biological evaluation.

Oxidative stress (OS) and disturbed intracellular redox balance have been predominantly observed in different types of cancer, including hepatocellular carcinoma (HCC). Agents which can stop OS multi-stressor events and modulate the intracellular redox state are becoming a major focus in HCC prevention. Among them, compounds with glutathione peroxidase (GPx)-like activity are of particularly concern. We herein report the synthesis of novel series of organoselenocyanates and symmetrical diselenide antioxidants, inspired by the natural redox enzyme, GPx and the synthetic organoselenium ebselen antioxidants. Their cytotoxic activity was evaluated against Hep G2 cells and their antimicrobial activities were evaluated against Candida albicans (C. albicans) fungus as well as against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), gram-negative and gram-positive bacteria, respectively. These compounds were also tested for their antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), GPx-like activity and bleomycin dependent DNA damage assays and a basic structure-activity relationship was subsequently established. The physicochemical parameters and drug-likeness were computed employing the Molinspiration online property calculation toolkit and MolSoft software. Interestingly, some compounds proved to be more cytotoxic than ebselen and the known anticancer drug 5-Fu and in the same time they showed similar, sometime even more, antifungal activity than the reference antifungal drugs. Among these compounds, compound 16 was considered to be the most interesting with free radical-scavenging activity comparable to ascorbic acid and a GPx-like activity similar to ebselen. As most of these compounds comply with Lipinski's Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.

Straightforward preparation of labeled potassium cyanate by ozonation and application to the synthesis of [13C] or [14C]ureidocarboxylic acids.

The development of new efficient syntheses of labeled reagents is a great challenge. Avoidance of overcomplicated procedures, availability and cost of starting materials are important considerations in choosing the synthetic route. In this report, we describe a facile and rapid preparation of labeled cyanate by ozonation of cyanide, a basic precursor. The crude cyanate was used without purification for the synthesis of various [(13)C] or [(14)C]ureidocarboxylic acids (20-68% yield from potassium cyanide). According to these results, cyanide ozonation may prove to be a promising alternative to traditional preparations of labeled cyanate.

Oxidation of thiocyanate with H2O2 catalyzed by [Ru(III)(edta)(H2O)]-.

The [Ru(III)(edta)(H2O)](-) (edta(4-) = ethylenediaminetetraacetate) complex is shown to catalyze the oxidation of thiocyanate (SCN(-)) with H2O2 mimicking the action of peroxidases. The kinetics of the catalytic oxidation process was studied by using stopped-flow and rapid scan spectrophotometry as a function of [Ru(III)(edta)], [H2O2], [SCN(-)], pH (3.2-9.1) and temperature (15-30 °C). Spectral analyses and kinetic data are suggestive of a catalytic pathway in which hydrogen peroxide reacts directly with thiocyanate coordinated to the Ru(III)(edta) complex. Catalytic intermediates such as [Ru(III)(edta)(OOH)](2-) and [Ru(V)(edta)(O)](-) were found to be non-reactive in the oxidation process under the specified conditions. Formation of SO4(2-) and OCN(-) was identified as oxidation products in ESI-MS experiments. A detailed mechanism in agreement with the spectral and kinetic data is presented.

Synthesis, characterization, and cure chemistry of renewable bis(cyanate) esters derived from 2-methoxy-4-methylphenol.

A series of renewable bis(cyanate) esters have been prepared from bisphenols synthesized by condensation of 2-methoxy-4-methylphenol (creosol) with formaldehyde, acetaldehyde, and propionaldehyde. The cyanate esters have been fully characterized by infrared spectroscopy, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. These compounds melt from 88 to 143 °C, while cured resins have glass transition temperatures from 219 to 248 °C, water uptake (96 h, 85 °C immersion) in the range of 2.05-3.21%, and wet glass transition temperatures from 174 to 193 °C. These properties suggest that creosol-derived cyanate esters may be useful for a wide variety of military and commercial applications. The cure chemistry of the cyanate esters has been studied with FTIR spectroscopy and differential scanning calorimetry. The results show that cyanate esters with more sterically demanding bridging groups cure more slowly, but also more completely than those with a bridging methylene group. In addition to the structural differences, the purity of the cyanate esters has a significant effect on both the cure chemistry and final Tg of the materials. In some cases, post-cure of the resins at 350 °C resulted in significant decomposition and off-gassing, but cure protocols that terminated at 250-300 °C generated void-free resin pucks without degradation. Thermogravimetric analysis revealed that cured resins were stable up to 400 °C and then rapidly degraded. TGA/FTIR and mass spectrometry results showed that the resins decomposed to phenols, isocyanic acid, and secondary decomposition products, including CO2. Char yields of cured resins under N2 ranged from 27 to 35%, while char yields in air ranged from 8 to 11%. These data suggest that resins of this type may potentially be recycled to parent phenols, creosol, and other alkylated creosols by pyrolysis in the presence of excess water vapor. The ability to synthesize these high temperature resins from a phenol (creosol) that can be derived from lignin, coupled with the potential to recycle the composites, provides a possible route to the production of sustainable, high-performance, thermosetting resins with reduced environmental impact.

In vitro effect on cancer cells: synthesis and preparation of polyurethane membranes for controlled delivery of curcumin.

Urethane polymers (PU) have been prepared from low-molecular weight polylactic acid (PLA) and hexamethylene diisocyanate (HMDI) using polydimethylsiloxane (PDMS) as a chain extender. These formed the supporting polymeric matrix of curcumin-containing PU membranes which were prepared using a solvent evaporation technique. FTIR and XRD data indicated the molecular-level dispersion and random distribution of curcumin in the polymer matrix, and data were consistent with observations from tensile-strength measurements and from AFM imaging. Determination of water vapor permeability and moisture uptake measurements have indicated that the PU membrane were appropriate for use on human skin. Skin permeation studies of curcumin were consistent with zero order (R² = 0.9874) and with Korsmeyer-Peppas (R² = 0.9978) kinetics-analytical data pointed to permeation by a combination of diffusion and erosion processes, with the latter dominating. The biocompatibility of these PU membranes was indicated by in vitro cytotoxicity studies using 3T3-L1-murine fibroblast cell. The in vitro therapeutic potential of the patches was demonstrated against A549 human lung cancer cells.

Selenocyanates and diselenides: a new class of potent antileishmanial agents.

Thirty five selenocyanate and diselenide compounds were subjected to in vitro screening against Leishmania infantum promastigotes and the most active ones were also tested in an axenic amastigote model. In order to establish the selectivity indexes (SI) the cytotoxic effect of each compound was also assayed against Jurkat and THP-1 cell lines. Thirteen derivatives exhibit better IC(50) values than miltefosine and edelfosine. Bis(4-aminophenyl)diselenide exhibits the best activity when assayed in infected macrophages and one of the lowest cytotoxic activities against the human cell lines tested, with SI values of 32 and 24 against Jurkat and THP-1 cells, respectively. This compound thus represents a new lead for further studies aimed at establishing its mechanism of action.

Applications of the ETS-NOCV method in descriptions of chemical reactions.

The present study characterizes changes in the electronic structure of reactants during chemical reactions based on the combined charge and energy decomposition scheme, ETS-NOCV (extended transition state-natural orbitals for chemical valence). Decomposition of the activation barrier, ΔE (#), into stabilizing (orbital interaction, ΔE (orb), and electrostatic, ΔE (elstat)) and destabilizing (Pauli repulsion, ΔE (Pauli), and geometry distortion energy, ΔE (dist)) factors is discussed in detail for the following reactions: (I) hydrogen cyanide to hydrogen isocyanide, HCN → CNH isomerization; (II) Diels-Alder cycloaddition of ethene to 1,3-butadiene; and two catalytic processes, i.e., (III) insertion of ethylene into the metal-alkyl bond using half-titanocene with phenyl-phenoxy ligand catalyst; and (IV) B-H bond activation catalyzed by an Ir-containing catalyst. Various reference states for fragments were applied in ETS-NOCV analysis. We found that NOCV-based deformation densities (Δρ (i)) and the corresponding energies ΔE (orb)(i) obtained from the ETS-NOCV scheme provide a very useful picture, both qualitatively and quantitatively, of electronic density reorganization along the considered reaction pathways. Decomposition of the barrier ΔE(#) into stabilizing and destabilizing contributions allowed us to conclude that the main factor responsible for the existence of positive values of ΔE (#) for all processes (I, II, III and IV) is Pauli interaction, which is the origin of steric repulsion. In addition, in the case of reactions II, III and IV, a significant degree of structural deformation of the reactants, as measured by the geometry distortion energy, plays an important role. Depending on the reaction type, stabilization of the transition state (relatively to the reactants) originating either from the orbital interaction term or from electrostatic attraction can be of vital importance. Finally, use of the ETS-NOCV method to describe catalytic reactions allows extraction of information on the role of catalysts in determination of ΔE (#).

Synthesis and characterization of oriented glyco-capturing macroligand.

An oriented glyco-capturing macroligand was synthesized by site-specific immobilization of an O-cyanate chain-end-functionalized boronic acid containing polymer (boropolymer) onto an amine surface. The O-cyanate chain-end-functionalized boropolymer was synthesized by arylamine-initiated cyanoxyl-mediated free-radical polymerization in a one-pot fashion. The chain-end O-cyanate was confirmed by (13)C NMR spectroscopy. The specific carbohydrate-binding capacity of the boropolymer was evaluated by an alizarin red S assay. Oriented and covalent immobilization of the O-cyanate chain-end-functionalized boropolymer onto the amine-modified solid surfaces and its specific glyco-capturing capacity were confirmed by the quartz crystal microbalance (QCM) and atomic force microscopy (AFM) techniques. The oriented multivalent glyco-capturing ligand can be used for efficient carbohydrate and glycoconjugate purification and identification, and thus is expected to constitute a core strategy of glycomics and glycoproteomics and carbohydrate-sensing applications.

DNA nucleobase synthesis at Titan atmosphere analog by soft X-rays.

Titan, the largest satellite of Saturn, has an atmosphere chiefly made up of N(2) and CH(4) and includes traces of many simple organic compounds. This atmosphere also partly consists of haze and aerosol particles which during the last 4.5 gigayears have been processed by electric discharges, ions, and ionizing photons, being slowly deposited over the Titan surface. In this work, we investigate the possible effects produced by soft X-rays (and secondary electrons) on Titan aerosol analogs in an attempt to simulate some prebiotic photochemistry. The experiments have been performed inside a high vacuum chamber coupled to the soft X-ray spectroscopy beamline at the Brazilian Synchrotron Light Source, Campinas, Brazil. In-situ sample analyses were performed by a Fourier transform infrared spectrometer. The infrared spectra have presented several organic molecules, including nitriles and aromatic CN compounds. After the irradiation, the brownish-orange organic residue (tholin) was analyzed ex-situ by gas chromatographic (GC/MS) and nuclear magnetic resonance ((1)H NMR) techniques, revealing the presence of adenine (C(5)H(5)N(5)), one of the constituents of the DNA molecule. This confirms previous results which showed that the organic chemistry on the Titan surface can be very complex and extremely rich in prebiotic compounds. Molecules like these on the early Earth have found a place to allow life (as we know) to flourish.

Bimetallic M(V)(2)Cu(II)(3) (M = Mo, W) coordination complexes based on octacyanometalates: structures and magnetic variations tuned by chelated tetradentate macrocyclic ligands.

Four octacyanometalate-based bimetallic Cu-M (M = Mo, W) assemblies coordinated by tetradentate macrocyclic ligands were prepared via self-assembly process in a stoichiometric ratio of [M(CN)8]3- and Cu(macrocycle)2+ and characterized in terms of structures and magnetic properties. The crystal structures are varied depending on the macrocycles used. The employment of cyclam with no pendant groups produced a one-dimensional chain (1) with a rope-ladder pattern, whereas macrocycles with side groups allowed for the formation of two-dimensional honeycomb-like architectures (2-4). From the crystal structures, the variations in apical Cu-Nax lengths and Cu-Nax-Cax angles on the bridging pathways are observed, which arises from the existence of side groups on macrocyclic ligands. The magnetic results reveal that all of the prepared compounds show ferromagnetic couplings between magnetic centers transimitted through CN bridges under the present structural parameters. Comparing the magnetic strength of the Cu-Mo (3d-4d; 2) and Cu-W (3d-5d; 3) complexes supports that 3d-5d magnetic coupling is stronger than 3d-4d because the 5d orbital is more diffuse than 4d. The magnetic analyses for 1-4 and related complexes tentatively suggest that, when the Cu-Nax distances are long enough, the axial Cu-Nax bond length in the bridging route may be one of the major structural parameters to determine the magnitude of the ferromagnetic exchange coupling.

Synthesis of HMDI-based segmented polyurethanes and their use in the manufacture of elastomeric composites for cardiovascular applications.

For short-term cardiovascular application, segmented polyurethanes (SPUs) based on 4,4-methylenebis(cyclohexyl isocyanate) (HMDI), polytetramethylenglycol (PTMG) and 1,4-butanediol (BD) were synthesized and characterized by spectroscopy (FT-IR, (1)H-NMR) and thermal (TGA, DMA, DSC) and mechanical techniques. The segmented nature of the SPUs was not easily established by spectroscopic means; however, TGA allowed the quantification of the rigid segments content by the significant mass loss between 348 and 356 degrees C. The alpha transition was detected by DMA and related to the T(g) of the soft segments at -50 degrees C, while DSC showed the presence of an endothermic transition above 80 degrees C attributed to the melting of rigid segments. Two types of composites were prepared using the synthesized SPUs and Lycra (either T162B or T162C). The first one consisted of a two layers casting laminated while the second one was a classic unidirectional fibre-reinforced material. Laminate composites prepared with SPU containing 23.9% and 33.9% of rigid segments and Lycra T162C exhibited a higher tensile modulus but lower tensile strength than composites prepared with Tecoflex SG-80A (39.7% of rigid segments). The energy of adhesion between layers on these composites ranged from 475 to 2150 J. Fibre-reinforced SPUs exhibited higher moduli than the two layer laminated composites with increasing amounts of rigid segments in the matrix and by increasing Lycra T162C content (up to 10%). This behaviour was explained by SEM, which showed a good fibre-matrix bonding.