Fast Fluoroalkylation of Proteins Uncovers the Structure and Dynamics of Biological Macromolecules.

Covalent labeling of proteins in combination with mass spectrometry has been established as a complementary technique to classical structural methods, such as X-ray, NMR, or cryogenic electron microscopy (Cryo-EM), used for protein structure determination. Although the current covalent labeling techniques enable the protein solvent accessible areas with sufficient spatial resolution to be monitored, there is still high demand for alternative, less complicated, and inexpensive approaches. Here, we introduce a new covalent labeling method based on fast fluoroalkylation of proteins (FFAP). FFAP uses fluoroalkyl radicals formed by reductive decomposition of Togni reagents with ascorbic acid to label proteins on a time scale of seconds. The feasibility of FFAP to effectively label proteins was demonstrated by monitoring the differential amino acids modification of native horse heart apomyoglobin/holomyoglobin and the human haptoglobin-hemoglobin complex. The obtained data confirmed the Togni reagent-mediated FFAP is an advantageous alternative method for covalent labeling in applications such as protein footprinting and epitope mapping of proteins (and their complexes) in general. Data are accessible via the ProteomeXchange server with the data set identifier PXD027310.

Intermolecular Interaction in Methylene Halide (CH2F2, CH2Cl2, CH2Br2 and CH2I2) Dimers.

The intermolecular interaction in difluoromethane, dichloromethane, dibromomethane, and diiodomethane dimers has been investigated using high level quantum chemical methods. The potential energy curve of intermolecular interaction along the C⋯C bond distance obtained using the coupled-cluster theory with singles, doubles, and perturbative triples excitations CCSD(T) were compared with values given by the same method, but applying the local (LCCSD(T)) and the explicitly correlated (CCSD(T)-F12) approximations. The accuracy of other theoretical methods-Hartree-Fock (HF), second order Møller-Plesset perturbation (MP2), and dispersion corrected DFT theory-were also presented. In the case of MP2 level, the canonical and the local-correlation cases combined with the density-fitting technique (DF-LMP2)theories were considered, while for the dispersion-corrected DFT, the empirically-corrected BLYP-D and the M06-2Xexchange-correlation functionals were applied. In all cases, the aug-cc-pVTZ basis set was used, and the results were corrected for the basis set superposition error (BSSE) using the counterpoise method. For each molecular system, several dimer geometries were found, and their mutual orientations were compared with the nearest neighbor orientations obtained in recent neutron scattering studies. The nature of the intermolecular interaction energy was discussed.

Characterization of the suspension stability of pharmaceuticals using a shadowgraphic imaging method.

A new shadowgraphic imaging method and an associated instrument for analyzing the physical stability of pharmaceutical suspensions are introduced in this paper. The new suspension tester consists mainly of a high-resolution camera that takes sequential shadowgraphic images of emulsions or suspensions and a 2D collimated LED for simultaneous whole-sample illumination in bright field. A built-in ultrasonic bath provides controlled initial agitation to the samples of interest. Sequential images acquired by the experimental setup were used to derive normalized transmission profiles from which an instability index was developed for quantitative stability comparison between samples. Instrument performance was verified by measuring the stability of a series of oil-in-water emulsions prepared with surfactant mixtures of different ratios. The new instrument correctly determined the required hydrophilic-lipophilic balance for sunflower oil to be 7.0. The stability of a pressurized suspension of spray dried lipid (DSPC) particles was monitored for 5 days after propellant filling. Although stable for the first 24 h, the lipid suspension was found to decrease in stability from day 1 to day 4. Morphological and spectroscopic analysis revealed that the suspended DSPC particles had reformed into large thin sheets of lipid, thereby causing the gradual stability decrease during the aging study. The effects of initial agitation on the stability of suspensions were demonstrated by agitating a suspension of micronized fluticasone propionate in propellant using a wrist action shaker and an ultrasonic bath respectively. A significant improvement of suspension stability was achieved by replacing the wrist action shaker method with ultrasonic agitation. Simultaneous illumination of the complete suspension, a high image acquisition rate, and controlled initial agitation are features that make this new suspension tester a suitable and more reliable instrument for investigating the stability of pressurized pharmaceutical suspensions.

Cholesterol Unbound RORγt Protein Enables a Sensitive Inverse Agonist Screening.

The retinoic acid-related orphan receptor gamma T (RORγt) plays an important role in Th17 cell proliferation and functionality. Thus, RORγt inverse agonists are thought to be potent therapeutic agents for Th17-mediated autoimmune diseases, such as rheumatoid arthritis, asthma, inflammatory bowel disease, and psoriasis. Although RORγt has constitutive activity, it is recognized that the receptor is physiologically regulated by various cholesterol derivatives. In this study, we sought to identify RORγt inverse agonists through a high-throughput screening campaign. To this end, we compared an apo-RORγt protein from Escherichia coli and a cholesterol-bound RORγt protein from insect cells. The IC50 of the known RORγt inverse agonist TO901317 was significantly lower for the apoprotein than for the cholesterol-bound RORγt. Through high-throughput screening using a fluorescence-based cholesterol binding assay with the apoprotein, we identified compound 1 as a novel cholesterol-competitive RORγt inverse agonist. Compound 1 inhibited the RORγt-TopFluor cholesterol interaction, coactivator recruitment, and transcriptional activity of RORγt. Cell-based reporter gene assay demonstrated that compound 1 showed higher potency by lipid depletion treatment. Collectively, our findings indicate that eliminating cholesterol from the RORγt protein is suitable for sensitive high-throughput screening to identify RORγt inverse agonists.

Flow injection spectrophotometric determination of V(V) involving on-line separation using a poly(vinylidene fluoride-co-hexafluoropropylene)-based polymer inclusion membrane.

A poly(vinylidene fluoride-co-hexafluoropropylene)-based polymer inclusion membrane (PIM) using Cyphos® IL 101 (i.e. trihexyl(tetradecyl)phosphonium chloride) as the carrier and 2-nitrophenyl octyl ether as a plasticizer in a mass ratio of 55/35/10 was employed for the on-line extractive separation of V(V) prior to its spectrophotometric determination in a flow injection analysis (FIA) system using xylenol orange as the colorimetric reagent. The selectivity of the membrane allowed the determination of V(V) in sulfate solutions in the presence of a variety of cations and anions. The interference of molybdenum(VI) was eliminated by off-line extraction using the same PIM. A univariate sequential optimization of the newly developed FIA system was conducted and under optimal conditions the system is characterized by a linear concentration range of 0.5-8.0mgL-1, detection limit of 0.08mgL-1 and sample throughput of 4h-1. The relative standard deviation at the 3mgL-1 level of V(V) was 2.9% based on 8 replicate determinations. The membrane was stable, which was reflected by the standard deviation value for determinations over three consecutive days (24 determinations of 3mgL-1 V(V)) of 3.6%. The newly developed FIA system was applied to the determination of V(V) in water and dietary supplements samples and a good agreement with inductively coupled plasma optical emission spectrometry was observed.

Flexible nanofilms coated with aligned piezoelectric microfibers preserve the contractility of cardiomyocytes.

The use of engineered cardiac tissue for high-throughput drug screening/toxicology assessment remains largely unexplored. Here we propose a scaffold that mimics aspects of cardiac extracellular matrix while preserving the contractility of cardiomyocytes. The scaffold is based on a poly(caprolactone) (PCL) nanofilm with magnetic properties (MNF, standing for magnetic nanofilm) coated with a layer of piezoelectric (PIEZO) microfibers of poly(vinylidene fluoride-trifluoroethylene) (MNF+PIEZO). The nanofilm creates a flexible support for cell contraction and the aligned PIEZO microfibers deposited on top of the nanofilm creates conditions for cell alignment and electrical stimulation of the seeded cells. Our results indicate that MNF+PIEZO scaffold promotes rat and human cardiac cell attachment and alignment, maintains the ratio of cell populations overtime, promotes cell-cell communication and metabolic maturation, and preserves cardiomyocyte (CM) contractility for at least 12 days. The engineered cardiac construct showed high toxicity against doxorubicin, a cardiotoxic molecule, and responded to compounds that modulate CM contraction such as epinephrine, propranolol and heptanol.

Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide.

Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets-GABAA receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABAA receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor.

Fluorinated ß-Diketo Phosphorus Ylides Are Novel Inhibitors of the ABCB1 Efflux Pump of Cancer Cells.

Efflux pump inhibitors are attractive compounds that reverse multidrug resistance (MDR) in cancer cells. In the present study, 10 phosphorus ylides (P-ylides) were compared based on their MDR-reverting activity in human ATP-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) gene-transfected L5178Y mouse T-lymphoma cells. Among them, three P-ylides, Ph3P=C(COCF3)COPh, Ph3P=C(COC2F5)COPh and Ph3P=C(COC3F7)COPh were identified as selectively modulating the ABCB1 pump. These compounds, with low cytotoxicity against mouse T-lymphoma cells, exhibited more potency than the positive control ABCB1 inhibitor verapamil.

Shelf-stable electrophilic reagents for trifluoromethylthiolation.

Fluorine, which is the most electronegative element and has a small atomic radius, plays a key role in pharmaceutical, agrochemical, and materials sciences. One of the fluoroalkyl groups, the trifluoromethylthio group (CF3S-), has been well-recognized as an important structural motif in the design of lead compounds for new drug discovery because of its high lipophilicity (Hansch lipophilicity parameter π = 1.44) and strong electron-withdrawing properties, which could improve the drug molecule's cell-membrane permeability and enhance its chemical and metabolic stability. While classic methods for the preparation of trifluoromethylthiolated compounds typically involve halogen-fluorine exchange reactions of polyhalogenomethyl thioethers or trifluoromethylation of sulfur-containing compounds under harsh reaction conditions, an alternative but more attractive strategy is direct trifluoromethylthiolation of the substrate at a late stage by employing an electrophilic trifluoromethylthiolating reagent. Although several electrophilic trifluoromethylthiolating reagents have been reported previously, these reagents either require a strong Lewis acid/Brønsted acid as an activator or suffer from a toxic nature or limited substrate scope. To address these problems, in late 2011 we initiated a project with the aim to develop new, shelf-stable, and highly reactive electrophilic trifluoromethylthiolating reagents that could easily install the trifluoromethylthio group at the desired positions of the drug molecule at a late stage of drug development. Inspired by the broad reactivity of the hypervalent iodine reagent, we initially discovered a highly reactive trifluoromethylthiolating reagent, trifluoromethanesulfenate 1a. Structure-reactivity studies disclosed that the iodine atom of reagent 1a does not play an important role in this reagent's reactivity. Consequently, a simplified second-generation electrophilic reagent, trifluoromethanesulfenate 1b, was developed. In parallel, we developed another shelf-stable, highly reactive electrophilic reagent with a broad substrate scope, N-trifluoromethylthiosaccharin (2). In this Account, we mainly describe our discovery of these two different types of electrophilic trifluoromethylthiolating reagents, trifluoromethanesulfenates 1a and 1b and N-trifluoromethylthiosaccharin 2. Systematic studies showed that both types of reagents are highly reactive toward a wide range of nucleophiles, yet the substrate scopes of these two different types of reagents are complementary. In particular, reagents 1a and 1b are more reliable in transition-metal-catalyzed reactions such as copper-catalyzed trifluoromethylthiolation of aryl/vinyl/alkylboronic acids and silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids as well as in the organocatalytic asymmetric trifluoromethylthiolation of ß-keto esters and oxindoles. Reagent 2 is more electrophilic than reagents 1a and 1b and is more efficient for direct trifluoromethylthiolation with nucleophiles such as alcohols, amines, thiols, and electron-rich arenes. The ease in preparation, broad scope, and mild reaction conditions make reagents 1a, 1b, and 2 very attractive as general reagents that allow rapid installation of the trifluoromethylthio group into small molecules.

Oxidative trifluoromethylation and trifluoromethylthiolation reactions using (trifluoromethyl)trimethylsilane as a nucleophilic CF3 source.

The trifluoromethyl group is widely prevalent in many pharmaceuticals and agrochemicals because its incorporation into drug candidates could enhance chemical and metabolic stability, improve lipophilicity and bioavailability, and increase the protein bind affinity. Consequently, extensive attention has been devoted toward the development of efficient and versatile methods for introducing the CF3 group into various organic molecules. Direct trifluoromethylation reaction has become one of the most efficient and important approaches for constructing carbon-CF3 bonds. Traditionally, the nucleophilic trifluoromethylation reaction involves an electrophile and the CF3 anion, while the electrophilic trifluoromethylation reaction involves a nucleophile and the CF3 cation. In 2010, we proposed the concept of oxidative trifluoromethylation: the reaction of nucleophilic substrates and nucleophilic trifluoromethylation reagents in the presence of oxidants. In this Account, we describe our recent studies of oxidative trifluoromethylation reactions of various nucleophiles with CF3SiMe3 in the presence of oxidants. We have focused most of our efforts on constructing carbon-CF3 bonds via direct trifluoromethylation of various C-H bonds. We have demonstrated copper-mediated or -catalyzed or metal-free oxidative C-H trifluoromethylation of terminal alkynes, tertiary amines, arenes and heteroarenes, and terminal alkenes. Besides various C-H bonds, aryl boronic acids proved to be viable nucleophilic coupling partners for copper-mediated or -catalyzed cross-coupling reactions with CF3SiMe3. To further expand the reaction scope, we also applied H-phosphonates to the oxidative trifluoromethylation system to construct P-CF3 bonds. Most recently, we developed silver-catalyzed hydrotrifluoromethylation of unactivated olefins. These studies explore boronic acids, C-H bonds, and P-H bonds as novel nucleophiles in transition-metal-mediated or -catalyzed cross-coupling reactions with CF3SiMe3, opening new viewpoints for future trifluoromethylation reactions. Furthermore, we also achieved the oxidative trifluoromethylthiolation reactions of aryl boronic acids and terminal alkynes to construct carbon-SCF3 bonds by using CF3SiMe3 and elemental sulfur as the nucleophilic trifluoromethylthiolating reagent. These oxidative trifluoromethylation and trifluoromethylthiolation reactions tolerate a wide range of functional groups, affording a diverse array of CF3- and CF3S-containing compounds with high efficiencies, and provide elegant and complementary alternatives to classical trifluoromethylation and trifluoromethylthiolation reactions. Because of the importance of the CF3 and SCF3 moieties in pharmaceuticals and agrochemicals, these reactions would have potential applications in the life science fields.

Predicting partition coefficients of Polyfluorinated and organosilicon compounds using polyparameter linear free energy relationships (PP-LFERs).

The environmental behavior, fate, and effects of polyfluorinated compounds (PFCs) and organosilicon compounds (OSCs) have received increasing attention in recent years. In this study, polyparameter linear free energy relationships (PP-LFERs) were evaluated for predicting partition coefficients of neutral PFCs and OSCs, using experimental data for fluorotelomer alcohols (FTOHs) and cyclic volatile methylsiloxanes (cVMS) reported in the literature and measured newly for this work. It was found that the recently proposed PP-LFER model that uses the McGowan characteristic volume (V), the logarithmic hexadecane-air partition coefficient (L), and three polar interaction descriptors can accurately describe partition coefficients of PFCs and OSCs. The prediction errors were <1 log unit when literature descriptors were used, and the errors were reduced to <0.2 log units on average by further optimization of the descriptors. Surprisingly, the conventional forms of PP-LFERs that include the excess molar refraction (E) sometimes led to substantial errors (>1 log unit) even with optimized parameters. The system parameters for octanol-water, air-water, octanol-air, oil-water, liposome-water, and organic carbon-water partition coefficients as well as the solute descriptors for FTOHs and cVMS were recalibrated in this work, which should provide even more reliable predictions of partition coefficients. The results also confirm the consistency of the published experimental partition coefficients for FTOHs and cVMS.

Kinetics studies of the reactions of main fourth-period monocations (Ga+, Ge+, As+, and Se+) with methyl fluoride.

Thermodynamics and kinetics theoretical studies on the gas-phase reactions of fluoromethane with main fourth-period monocations (Ga(+), Ge(+), As(+), and Se(+)) have been carried out. Density functional theory (in particular mPW1K functional) was employed in the description of the potential energy surfaces, and refinement of the energies were done at the CCSD(T) level. The reaction rate constants were estimated using variational/conventional microcanonical transition state theory. From a thermodynamic viewpoint, the fluorine abstraction product is predicted for Ga(+) and Ge(+), whereas for As(+) and Se(+) the elimination product, MCH2(+) (M = As, Se) + HF, is the preferred one. Nevertheless, the most favorable channel for the reactions of CH3F with Ga(+) and Se(+) cations present a net activation barrier. In the case of Ga(+), the reaction proceeds via an addition channel forming the adduct complex, CH3FGa(+), whereas for Se(+) no reaction is found, in agreement with the experiments. The predicted reaction rate constants are in reasonable good agreement with the experimental values available. Apart from the harpoon-like mechanism, our results suggest that an oxidative addition mechanism seems to play a relevant role.

Complementary regioselectivity in Rh(III)-catalyzed insertions of potassium vinyltrifluoroborate via C-H activation: preparation and use of 4-trifluoroboratotetrahydroisoquinolones.

Potassium vinyltrifluoroborate was found to be an efficient partner with benzamide derivatives for Rh(III)-catalyzed annulations. 4-Trifluoroboratotetrahydroisoquinolones were generated under mild conditions, affording a regioisomerically complementary substitution pattern to other alkenes in related reactions. These new boron-containing building blocks were derivatized by N-arylations, retaining the boron substituent for further elaboration.

The Lewis acidity of fluorophosphonium salts: access to mixed valent phosphorus(III)/(V) species.

Oxidative fluorination of the electron-deficient phosphine Ph(2)P(C(6)F(5)) using XeF(2), followed by fluoride ion abstraction from the resulting difluorophosphorane Ph(2)P(F)(2)(C(6)F(5)), produces electrophilic fluorophosphonium salts [Ph(2)P(F)(C(6)F(5))][X] (X = FB(C(6)F(5))(3) or O(3)SCF(3)). Variable temperature NMR spectroscopic analysis of [Ph(2)P(F)(C(6)F(5))][FB(C(6)F(5))(3)] demonstrates a fluxional process attributed to fluoride ion exchange between B(C(6)F(5))(3) and [Ph(2)P(F)(C(6)F(5))](+), suggesting that these species have comparable Lewis acidities. This exchange can also be illustrated by adding phosphine Ph(3)P to [Ph(2)P(F)(C(6)F(5))][FB(C(6)F(5))(3)] at ambient temperature to produce Ph(2)P(F)(2)(C(6)F(5)) and Ph(3)P-B(C(6)F(5))(3), while heating this mixture results in thermally induced para-substitution of Ph(3)P at the C(6)F(5) group of the phosphonium ion to generate [Ph(3)P(C(6)F(4))P(F)(2)Ph(2)][FB(C(6)F(5))(3)]. Such frustrated Lewis pair reactivity also can be exploited by reacting [Ph(2)P(F)(C(6)F(5))][O(3)SCF(3)] with silylphosphine Ph(2)PSiMe(3) to afford the unique mixed-valent salt [Ph(2)P(C(6)F(4))P(F)Ph(2)][O(3)SCF(3)], which upon the addition of fluoride is converted to Ph(2)P(C(6)F(4))P(F)(2)Ph(2). XeF(2) reacts with [Ph(2)P(C(6)F(4))P(F)Ph(2)][O(3)SCF(3)] at ambient temperature, producing equal proportions of the dicationic salt [Ph(2)P(F)(C(6)F(4))P(F)Ph(2)][O(3)SCF(3)](2) and the bis(difluorophosphorane) Ph(2)P(F)(2)(C(6)F(4))P(F)(2)Ph(2), the latter of which can then be quantitatively converted to the former by adding one equiv of Me(3)SiO(3)SCF(3).

A study of the efficacy and safety of ciclesonide hydrofluoroalkane nasal aerosol in patients with seasonal allergic rhinitis from mountain cedar pollen.

A nasal aerosol formulation of ciclesonide with a hydrofluoroalkane propellant (CIC-HFA) is currently in development for treatment of allergic rhinitis (AR). This study evaluated the efficacy and safety of once-daily administration of CIC-HFA 74 or 148 micrograms compared with placebo in patients with seasonal AR (SAR) from mountain cedar pollen. Patients ≥12 years of age with a ≥2-year history of SAR from mountain cedar pollen were randomized in a placebo-controlled, double-blind, parallel group, multicenter study to CIC-HFA 74 micrograms, CIC-HFA 148 micrograms, or placebo once daily in the morning for 2 weeks. Change from baseline in reflective total nasal symptom score (rTNSS), instantaneous TNSS (iTNSS), and reflective total ocular symptom score (rTOSS) in patients with baseline rTOSS ≥5.00 were evaluated. Adverse events (AEs) were monitored throughout the study. A statistically significant improvement in rTNSS (least squares [LS] mean change from baseline 1.04 and 1.02 respectively; p < 0.0001 versus placebo for both) and iTNSS (LS mean change from baseline 0.90 and 0.83 respectively; p < 0.001 vs placebo for both) was observed after treatment with CIC-HFA 74- or 148-microgram doses. Only the CIC-HFA 74-micrograms treatment group showed a statistically significant improvement in rTOSS (LS mean change from baseline 0.52; p = 0.0124) compared with placebo. The overall incidence of AEs was low and comparable between the treatment groups. In this study, statistically significant improvements in nasal symptoms of SAR were observed after treatment with CIC-HFA 74-microgram or CIC-HFA 148-microgram doses. Both active treatments were well tolerated. Clinical trial registry URL and registration number: www.clinicaltrials.gov/ct2/show/NCT01010971.

A novel bottom-up process to produce nanoparticles containing protein and peptide for suspension in hydrofluoroalkane propellants.

To overcome the disadvantages of microemulsion and nanoprecipitation methods to produce protein-containing nanoparticles, a novel bottom-up process was developed to produce nanoparticles containing the model protein lysozyme. The nanoparticles were generated by freeze-drying a solution of lysozyme, lecithin and lactose in tert-butyl alcohol (TBA)/water co-solvent system and washing off excess lecithin in lyophilizate by centrifugation. Formulation parameters such as lecithin concentration in organic phase, water content in TBA/water co-solvent, and lactose concentration in water were optimized so as to obtain desired nanoparticles with retention of the bioactivity of lysozyme. Based on the results, 24.0% (w/v) of lecithin, 37.5% (v/v) of water content, and 0.56% (w/v) of lactose concentration were selected to generate spherical nanoparticles with approximately 200 nm in mean size, 0.1 in polydispersity index (PI), and 99% retained bioactivity of lysozyme. These nanoparticles rinsed with ethanol containing dipalmitoylphosphatidylcholine (DPPC), Span 85 or oleic acid (3%, w/v) could readily be dispersed in HFA 134a to form a stable suspension with good redispersibility and 98% retained bioactivity of lysozyme. The study indicates there is a potential to produce pressed metered dose inhaler (pMDI) formulations containing therapeutic protein and peptide nanoparticles.

Potent and selective 5-LO inhibitor bearing benzothiophene pharmacophore: discovery of MK-5286.

The strategy and SAR studies that led to the discovery of a novel potent and orally available 5-lipoxygenase (5-LO) inhibitor 3-(4-fluorophenyl)-6-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-benzothiophene-2-carboxamide ((S)-2l or MK-5286) were described.

Syntheses, structures and photophysical properties of heterotrinuclear Zn2Ln clusters (Ln = Nd, Eu, Tb, Er, Yb).

Heterotrinuclear Zn(2)Ln (Ln = Nd 2, Eu 3, Tb 4, Er 5, Yb 6) clusters [(Znq(2))(2)](mu-CH(3)COO){Ln(hfac)(2)} (q = 8-hydroxylquinolinate, hfac = hexafluoroacetylacetonate) have been synthesized. The Zn(2)Ln framework is ligated by two q ligands featuring mu-phenoxo and two q ligands featuring mu(3)-phenoxo coordination modes, and one mu-CH(3)COO(-) anions. Since the short intramolecular separations of Zn...Ln (ca. 3.354-3.373 A) allow energy transfer from Znq(2)-based sensitizers to the Ln(III) centres through two energy transfer pathways, the lanthanide luminescence is indeed "lighted up" by excitation of the Znq(2)-based chromopores. Photophysical measurements revealed that these Zn(2)Ln complexes exhibit the so-called "dual emission" originating from both Znq(2)-based luminophores and lanthanide emitters. By virtue of the dual luminescence with complementary colours, the Znq(2)-based cyan emission and Eu(III)-centred red luminescence are combined to generate a white-light emission in the Zn(2)Eu (3) complex.

Al(OTf)(3)-mediated epoxide ring-opening reactions: toward piperazine-derived physiologically active products.

Al(OTf)(3) is a good catalyst for the ring opening of epoxides, forming beta-amino alcohols bearing the piperazine motif. Two different strategies were examined, where the glycidyl ether resided on one-half of the molecule or the other, allowing insight into a best-case approach for the ring-opening step. Each half of the molecule contained an heteroatom that could be used either to attach the glycidyl moiety or as the nucleophile in the ring-opening reaction, for the same set of reagents, allowing this approach.