Electronic and Magnetic Interactions in 6-Oxoverdazyl Diradicals: Connection through N(1) vs C(3) Revisited.

Four isomeric di-6-oxoverdazyl diradicals connected at their N(1) or C(3) positions with either 1,3- or 1,4-phenylene linkers were obtained and characterized by spectroscopic, electrochemical, magnetic, and structural methods. These results were compared to those for the corresponding 6-oxoverdazyl monoradicals. UV-vis spectroscopy demonstrated that only the N(1)-connected para-through-benzene diradical has a distinct spectrum with significant bathochromic and hypsochromic shifts relative to the remaining species. Electrochemical analysis revealed two one-electron reduction processes in all diradiacals, while only the N(1)-connected para-through-benzene diradical exhibits two one-electron oxidation processes separated by 0.10 V. Variable temperature EPR measurements in polystyrene solid solutions gave negative mean exchange interaction energies J for all diradicals, suggesting the dominance of conformers with significant intramolecular antiferromagnetic interactions for the meta-through-benzene isomers. DFT calculations predict a small preference for the triplet state with the ΔES-T of about 0.25 kcal mol-1 for both meta-through-benzene connected diradicals.

Elucidating mechanochemical reactivity of a ternary halogen-bonded cocrystal system by computational and calorimetric studies.

Discovery of a halogen-bonded ternary cocrystal of 1,3,5-trifluoro-2,4,6-triiodobenzene with pyrazine and triphenylphosphine sulfide has revealed a complex landscape of multicomponent phases, all achievable by mechanochemical interconversion. The observed solid-state reaction pathways were explained by periodic density-functional calculations and comprehensive intermolecular interaction analysis, supported by dissolution calorimetry measurements.

DFT stimulation and experimental insights of chiral Cu(II)-salen scaffold within the pocket of MWW-zeolite and its catalytic study.

A Cu(II)-salen complex encapsulated in MWW-framework as an efficient chiral organocatalyst was developed for the synthesis of 3,4-dihydropyrimidin-2-(1H)-one (DHPMs) derivatives via an asymmetric pathway. In order to confirm its structural properties, single-crystal X-ray diffraction, powder XRD, BET, XPS, FE-SEM, EDX, UV-Vis, and FTIR spectra were used. Using computer-assisted DFT calculations, the Cu(II)-salen complex has been fine-tuned to fit into the pocket of the porous MWW support while keeping its chirality. This organocatalyst was shown to be a potent catalyst for the formation of the desired DHPMs product under short reaction times. Furthermore, this green protocol allows rapid and simple isolation of active MWW-trapped Cu(II)-salen scaffolds and its reusability in at least five consecutive runs without losing much of its activity.

Micro-Evolutionary Processes in Armeria maritima at Metalliferous Sites.

Tolerance to heavy metals in plants is a model process used to study adaptations to extremely unfavorable environments. One species capable of colonizing areas with high contents of heavy metals is Armeria maritima (Mill.) Wild. A. maritima plants growing in metalliferous areas differ in their morphological features and tolerance levels to heavy metals compared to individuals of the same species growing in non-metalliferous areas. The A. maritima adaptations to heavy metals occur at the organismal, tissue, and cellular levels (e.g., the retention of metals in roots, enrichment of the oldest leaves with metals, accumulation of metals in trichomes, and excretion of metals by salt glands of leaf epidermis). This species also undergoes physiological and biochemical adaptations (e.g., the accumulation of metals in vacuoles of the root's tannic cells and secretion of such compounds as glutathione, organic acids, or HSP17). This work reviews the current knowledge on A. maritima adaptations to heavy metals occurring in zinc-lead waste heaps and the species' genetic variation from exposure to such habitats. A. maritima is an excellent example of microevolution processes in plants inhabiting anthropogenically changed areas.

The Structural Characterisation and DFT-Aided Interpretation of Vibrational Spectra for Cyclo(l-Cys-d-Cys) Cyclic Dipeptide in a Solid State.

Cyclic dipeptides with two intramolecular peptide bonds forming a six-membered 2,5-diketopiperazine ring are gaining significant attention due to their biological and chemical properties. Small changes in the local geometry of such molecules (from cis to trans) can lead to significant structural differences. This work presents the results of a study of cyclo(l-Cys-d-Cys), a dipeptide comprising two cysteine molecules in opposite chiral configurations, with the functional groups situated at both sides of the diketopiperazine ring. X-ray diffraction (XRD) experiment revealed that the molecule crystallises in the P-1 space group, which includes the centre of inversion. The IR and Raman vibrational spectra of the molecule were acquired and interpreted in terms of the potential energy distribution (PED) according to the results of density functional theory (DFT) calculations. The DFT-assisted analysis of energy frameworks for the hydrogen bond network within molecular crystals was performed to support the interpretation of X-ray structural data. The optimisation of the computational model based on three-molecule geometry sections from the crystallographic structure, selected to appropriately reflect the intermolecular interactions responsible for the formation of 1D molecular tapes in cyclo(l-Cys-d-Cys) crystal, allowed for better correspondence between theoretical and experimental vibrational spectra. This work can be considered the first complete structural characterisation of cyclo(l-Cys-d-Cys), complemented via vibrational spectroscopy results with full band assignment aided with the use of the DFT method.

Investigation of electrocatalytic activity of a new mononuclear Mn(II) complex for water oxidation in alkaline media.

Water splitting is a promising way to alleviate the energy crisis. In nature, water oxidation is done by a tetranuclear manganese cluster in photosystem II. Therefore, the study of water oxidation by Mn complexes is attractive in water splitting systems. In this report, a new mononuclear Mn(II) complex, MnL2 (HL = (E)-3-hydroxy-N'-(pyridin-2-ylmethylene)-2-naphthohydrazide) was prepared and characterized by spectroscopic techniques and single-crystal X-ray diffraction. Crystallographic analysis indicated that the geometry around the Mn(II) ion is distorted octahedral. The MnN4O2 coordination moiety is achieved by bounding of oxygen and two nitrogen donor atoms of two hydrazone ligands. The synthesized complex was also investigated for electrochemical water oxidation using electrochemical techniques, scanning electron microscopy, energy dispersive spectrometry, and PXRD analysis. Linear sweep voltammetry experiment showed that the modified carbon paste electrode by the complex displays high activity for water oxidation reaction with an overpotential of 565 mV at a current density of 10 mA cm-2 and Tafel slope of 105 mV dec-1 in an alkaline solution. It was found that the complex structure finally changes during the reaction and converts to Mn oxide nanoparticles which act as active catalytic species and oxidize the water.

Electronic Coupling in 1,2,3-Triazole Bridged Ferrocenes and Its Impact on Reactive Oxygen Species Generation and Deleterious Activity in Cancer Cells.

Mixed-valence (MV) binuclear ferrocenyl compounds have long been studied as models for testing theories of electron transfer and in attempts to design molecular-scale electronic devices (e.g., molecular wires). In contrary to that, far less attention has been paid to MV binuclear ferrocenes as anticancer agents. Herein, we discuss the synthesis of six 1,2,3-triazole ferrocenyl compounds for combined (spectro)electrochemical, electron paramagnetic resonance (EPR), computational, and anticancer activity studies. Our synthetic approach was based on the copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction and enabled us to obtain in one step compounds bearing either one, two, or three ferrocenyl entities linked to the common 1,2,3-triazole core. Thus, two series of complexes were obtained, which pertain to derivatives of 3'-azido-3'-deoxythymidine (AZT) and 3-azidopropionylferrocene, respectively. Based on the experimental and theoretical data, the two mono-oxidized species corresponding to binuclear AZT and trinuclear 3-azidopropionylferrocene complexes have been categorized as class II mixed-valence according to the classification proposed by Robin and Day. Of importance is the observation that these two compounds are more active against human A549 and H1975 non-small-cell lung cancer cells than their congeners, which do not show MV characteristics. Moreover, the anticancer activity of MV species competes or surpasses, dependent on the cell line, the activity of reference anticancer drugs such as cisplatin, tamoxifen, and 5-fluorouracil. The most active from the entire series of compounds was the binuclear thymidine derivative with the lowest IC50 value of 5 ± 2 µM against lung H1975 cancer cells. The major mechanism of antiproliferative activity for the investigated MV compounds is based on reactive oxygen species generation in cancer cells. This hypothesis was substantiated by EPR spin-trapping experiments and the observation of decreased anticancer activity in the presence of N-acetyl cysteine (NAC) free-radical scavenger.

Chemistry of glycol nucleic acid (GNA): Synthesis, photophysical characterization and insight into the biological activity of phenanthrenyl GNA constituents.

The knowledge pertaining to the chemistry and biological activity of glycol nucleic acid (GNA) components, like nucleosides and nucleotides, is still very limited. Herein we report on the preparation of the uracil nucleoside (1) and nucleotide ester GNA (2). The compounds are functionalised with a luminescent phenanthrenyl group. In DMSO, 1 and 2 are brightly fluorescent, with emission maxima at 390 nm, nanosecond decay times (0.6 and 0.75 ns, respectively), and quantum yields of ca. 0.2. In the solid phase, they show excimeric emission, with maxima at 495 nm (1) and 432 nm (2), and decay times of 3.7 ns (1) and 2.9 ns (2). The anticancer activity of the GNA components, as well as gemcitabine hydrochloride, used as a reference drug, were examined in vitro against human cancer HeLa and Ishikawa cells, as well as against normal L929 cells, using a battery of biochemical assays. Furthermore, biodistribution imaging studies were carried out in HeLa cells, with luminescence confocal microscopy, which showed that the compounds localized mainly in the lipophilic cellular compartments. Nucleoside (1) and nucleotide ester (2) features two different anticancer activity profiles. At 24 h of treatment, the nucleoside acts mainly as a toxin and induces necrosis in HeLa cells, whereas the nucleotide ester exhibits pro-apoptotic activity. At longer treatment times (72 h), the nucleoside and the reference, gemcitabine hydrochloride, featured almost identical signs of anticancer activity, such as S-phase cell cycle arrest, proliferation inhibition, and apoptosis induction. In view of this data, one can hypothesize that despite the structural differences, the newly obtained phenanthrenyl GNA nucleoside (1) and gemcitabine may share a common mechanism of anticancer activity in HeLa cancer cells. The GNA components were also examined as antiplasmodial agents against Plasmodium falciparum, in vitro. Nucleoside (1) was found to be more potent than nucleotide (2), displaying activity in the low micromolar range. Furthermore, both phenanthrene derivatives were found to display resistance indices at least 9-fold lower than chloroquine diphosphate (CQDP).

Heterobimetallic Coinage Metal-Ruthenium Complexes Supported by Anionic N-Heterocyclic Carbenes.

The lithium complexes [(WCA-NHC)Li(toluene)] of anionic N-heterocyclic carbenes with a weakly coordinating borate moiety (WCA-NHC, WCA=B(C6 F5 )3 , NHC=IDipp=1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) were used for the preparation of silver(I) or copper(I) WCA-NHC complexes. While the reactions in THF with AgCl or CuCl afforded anionic mono- and dicarbene complexes with solvated lithium counterions [Li(THF)n ]+ (n=3, 4), the reactions in toluene proceeded with elimination of LiCl and formation of the neutral phosphine and arene complexes [(WCA-NHC)M(PPh3 )] and [(WCA-NHC)M(η2 -toluene)] (M=Ag, Cu). The latter were used for the preparation of chlorido- and iodido-bridged heterobimetallic Ag/Ru and Cu/Ru complexes [(WCA-NHC)M(µ-X)2 Ru(PPh3 )(η6 -p-cymene)] (M=Ag, Cu, X=Cl; M=Ag, X=I). Surprisingly, these complexes resisted the elimination of CuCl, AgCl, or AgI, precluding WCA-NHC transmetalation.

Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents.

Currently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, (12aS)-8,9-dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione and (12aS)-8-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell lines when compared to our previously reported compounds, with IC50 values in the range of 2.9-5.6 µM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC50 =6.1 µM) and MV-4-11 (IC50 =11.0 µM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC50 =31.8-55.0 µM) and very weak cytotoxic effect toward the Balb/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had Ki values of 10-19 µM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies.

Experimental and Computational Studies on Structure and Energetic Properties of Halogen Derivatives of 2-Deoxy-D-Glucose.

The results of structural studies on a series of halogen-substituted derivatives of 2-deoxy-D-glucose (2-DG) are reported. 2-DG is an inhibitor of glycolysis, a metabolic pathway crucial for cancer cell proliferation and viral replication in host cells, and interferes with D-glucose and D-mannose metabolism. Thus, 2-DG and its derivatives are considered as potential anticancer and antiviral drugs. X-ray crystallography shows that a halogen atom present at the C2 position in the pyranose ring does not significantly affect its conformation. However, it has a noticeable effect on the crystal structure. Fluorine derivatives exist as a dense 3D framework isostructural with the parent compound, while Cl- and I-derivatives form layered structures. Analysis of the Hirshfeld surface shows formation of hydrogen bonds involving the halogen, yet no indication for the existence of halogen bonds. Density functional theory (DFT) periodic calculations of cohesive and interaction energies (at the B3LYP level of theory) have supported these findings. NMR studies in the solution show that most of the compounds do not display significant differences in their anomeric equilibria, and that pyranose ring puckering is similar to the crystalline state. For 2-deoxy-2-fluoro-D-glucose (2-FG), electrostatic interaction energies between the ligand and protein for several existing structures of pyranose 2-oxidase were also computed. These interactions mostly involve acidic residues of the protein; single amino-acid substitutions have only a minor impact on binding. These studies provide a better understanding of the structural chemistry of halogen-substituted carbohydrates as well as their intermolecular interactions with proteins determining their distinct biological activity.

Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile.

Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor-tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 µM) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents.

A competition between hydrophobic and electrostatic interactions in protein-ligand systems. Binding of heterogeneously halogenated benzotriazoles by the catalytic subunit of human protein kinase CK2.

A series of chlorine-substituted benzotriazole derivatives, representing all possible substitution patterns of halogen atoms attached to the benzotriazole benzene ring, were synthetized as potential inhibitors of human protein kinase CK2. Basic ADME parameters for the free solutes (hydrophobicity, electronic properties) together with their binding affinity to the catalytic subunit of protein kinase CK2 were determined with reverse-phase HPLC, spectrophotometric titration, and Thermal Shift Assay Method, respectively. The analysis of position-dependent thermodynamic contribution of a chlorine atom attached to the benzotriazole ring confirmed the previous observation for brominated benzotriazoles, in which substitution at positions 5 and 6 with bromine was found crucial for ligand binding. In all tested halogenated benzotriazoles the replacement of Br with Cl decreases the hydrophobicity, while the electronic properties remain virtually unaffected. Supramolecular architecture identified in the just resolved crystal structures of three of the four possible dichloro-benzotriazoles shows how substitution distant from the triazole ring affects the pattern of intermolecular interactions. Summarizing, the benzotriazole benzene ring substitution pattern has been identified as the main driver of ligand binding, predominating the non-specific hydrophobic effect.

In a Quest for Selectivity Paired with Activity: A Ruthenium Olefin Metathesis Catalyst Bearing an Unsymmetrical Phenanthrene-Based N-Heterocyclic Carbene.

Robust, selective, and stable in the presence of ethylene, ruthenium olefin metathesis pre-catalyst, {[3-benzyl-1-(10-phenyl-9-phenanthryl)]-2-imidazolidinylidene}dichloro(o-isopropoxyphenylmethylene)ruthenium(II), Ru-3, bearing an unsymetrical N-heterocyclic carbene (uNHC) ligand, has been synthesized. The initiation rate of Ru-3 was examined by ring-closing metathesis and cross-metathesis reactions with a broad spectrum of olefins, showing an unprecendented selectivity. It was also tested in industrially relevant ethenolysis reactions of olefinic substrates from renewable feedstock with very good yields and selectivities.

Synthesis, crystal structure and biological activity of novel analogues of tricyclic drugs.

A series of fourteen novel, eight-membered lactam- and dilactam-based analogues of tricyclic drugs were obtained in a simple one-pot procedure. Crystal structures of two compounds were determined by single-crystal X-ray diffraction analysis and their selected structural features were discussed and compared with those of imipramine and dibenzepine. Affinity of developed molecules for histamine receptor H1, serotonin receptors 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, serotonin transporter (SERT) and dopamine receptor D2 was determined. The commercial drug dibenzepine was also checked on these molecular targets, as its mechanism of action is largely unknown. Two derivatives of 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one (7,8) and two of dibenzo[b,f]azocin-6(5H)-one (9,10) were found to be active toward the H1 receptor in sub-micromolar concentrations.

Research into the oxidation of abietic acid-derived enone with atmospheric oxygen.

This work presents results of methyl 7-oxoabiet-13(14)-en-18-oate (3) self-oxidation with air-oxygen in the presence of various bases such as triethylamine or sodium t-butoxide. While under aerobic conditions, the use of sodium t-butoxide as a base results in the formation of four isomeric alcohols, an addition of triethylamine into reaction medium directs the enone 3 oxidation to hydroperoxides. To clarify this base dependence and to obtain more in-depth information about this reaction additional studies with cyclohexenone as a reference enone have been undertaken. Their results demonstrated the predisposition of abietane hydroperoxides to oxidize α,ß-unsaturated ketones to epoxides in the presence of t-butoxide while reducing the hydroperoxide group to hydroxyl. This ability of hydroperoxides to epoxidize conjugated double bonds and confirmed by the present study intermolecular course allowed proposing a plausible mechanism for this reaction.

Unsymmetrically Substituted Dibenzo[b,f][1,5]-diazocine-6,12(5H,11H)dione-A Convenient Scaffold for Bioactive Molecule Design.

A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development.

Unsymmetrically-Substituted 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione Scaffold-A Useful Tool for Bioactive Molecules Design.

Unsymmetrically N-substituted and N,N'-disubstituted 5,12-dihydrodibenzo [b,f][1,4]diazocine-6,11-diones were synthesized in the new protocol. The desired modifications of the dibenzodiazocine scaffold were introduced at the stages of proper selection of building blocks as well as post-cyclization modifications with alkylation or acylation agents, expanding the structural diversity and possible applications of synthesized molecules. The extension of developed method resulted in the synthesis of novel: tricyclic 5,10-dihydrobenzo[b]thieno[3,4-f][1,4]diazocine-4,11-dione scaffold and fused pentacyclic framework possessing two benzodiazocine rings within its structure. Additionally, the unprecedented rearrangement of 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-diones to 2-(2-aminophenyl)isoindoline-1,3-diones was observed under the basic conditions in the presence of sodium hydride for secondary dilactams. The structures of nine synthesized products have been established by single-crystal X-ray diffraction analysis. Detailed crystallographic analysis of the investigated tri- and pentacyclic systems has shed more light on their structural features. One cell line derived from non-cancerous cells (EUFA30-human fibroblasts) and three tumor cells (U87-human primary glioblastoma, HeLa-cervix adenocarcinoma, BICR18-laryngeal squamous cell carcinoma) were used to determine the cytotoxic effect of the newly synthesized compounds. Although these compounds showed a relatively weak cytotoxic effect, the framework obtained for 5,12-dihydrodibenzo[b,f][1,4]diazocine-6,11-dione could serve as a convenient privilege structure for the design and development of novel bioactive molecules suitable for drug design, development and optimization programs.

Luminescent pyrenyl-GNA nucleosides: synthesis, photophysics and confocal microscopy studies in cancer HeLa cells.

Glycol nucleic acids (GNA) are synthetic genetic-like polymers with an acyclic three-carbon propylene glycol phosphodiester backbone. Here, synthesis, luminescence properties, circular dichroism (CD) spectra, and confocal microscopy speciation studies of (R,S) and (S,R) pyrenyl-GNA (pyr-GNA) nucleosides are reported in HeLa cells. Enantiomerically pure nucleosides were obtained by a Sharpless asymmetric dihydroxylation reaction followed by semi-preparative high-performance liquid chromatography (HPLC) separation using Amylose-2 as the chiral stationary phase. The enantiomeric relationship between stereoisomers was confirmed by CD spectra, and the absolute configurations were assigned based on experimental and theoretical CD spectra comparisons. The pyr-GNA nucleosides were not cytotoxic against human cervical (HeLa) cancer cells and thus were utilized as luminescent probes in the imaging of these cells with confocal microscopy. Cellular staining patterns were identical for both enantiomers in HeLa cells. Compounds showed no photocytotoxic effect and were localized in the lipid membranes of the mitochondria, in cellular vesicles and in other lipid cellular compartments. The overall distribution of the pyrene and pyrenyl-GNA nucleosides inside the living HeLa cells differed, since the former compound gives a more granular staining pattern and the latter a more diffuse one.

Well-Defined Chiral Copper NHC Complex in the Asymmetric Conjugated ß-Borylation and One-Pot Metathesis-Asymmetric ß-Borylation Reactions.

Highly stereoselective conjugate ß-borylation, using a new chiral NHC-based copper catalyst, has been achieved. The chiral NHC copper complex was prepared in gram scale and showed high enantioselectivity and activity (up to 10 000 turnovers at 100 ppm of catalyst loading). This method was employed in the synthesis of a chiral ß-borylated ester from simple unconjugated alkenes though an unprecedented one-pot cross metathesis-asymmetric borylation sequence.