The synthesis of novel heteroaryl-fused 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Effective inhibitors of HCV NS5B polymerase

Three synthetic approaches have been developed that allow efficient access to novel heteroaryl fused indole ring systems, including: 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indoles, 4-oxo-2,3-dihydro-1H-[1,4]diazepino[1,7-a]indoles and 1,2,4,5-tetrahydro-[1,4]oxazepino[4,5-a]indoles. Each strategy is fully exemplified and the relative merits and limitations of the approaches are discussed. The hepatitis C virus (HCV) non-structural 5B (NS5B) polymerase inhibitory activities of select examples from each molecular class are briefly presented.     

Disorder in BaThF6--refinement of anharmonic displacement parameters from high-pressure single-crystal X-ray diffraction data

The structure of BaThF(6) has been investigated as a function of temperature and pressure with single-crystal X-ray diffraction using synchrotron radiation. The compound crystallizes in the tysonite structure, space group P6(3)/mmc (a = 4.296(1) ? and c = 7.571(1) ? at ambient conditions). It is stable at least down to 150 K and up to 4 GPa. In the entire range of pressures and temperatures studied here, the compound is characterized by a high degree of disorder, both on the cationic and anionic positions. Despite the different valence states and sizes, both cations occupy the same crystallographic site in the ideal tysonite structure. The cationic disorder is described by two alternative approaches. The first model corresponds to a split-atom position model in which Ba(2+) is maintained on a special position with site symmetry 6m2, while Th(4+) is slightly displaced from the respective position. In the second model, both cations are maintained on the ideal position and anharmonic displacement parameters using a tensor of third order are introduced. Anharmonic displacement parameters have been refined from high-pressure single-crystal X-ray data measured in situ in a diamond anvil cell for the first time. The feasibility and general problems of anharmonic refinements of high-pressure X-ray data are further commented.     

Unsymmetrical (R)PNP(R') pincer ligands and their group 10 complexes

Two new unsymmetrical (R)PNP(R')-type pincer ligands based on a bis(tolyl)amine framework have been synthesized and characterized by a variety of techniques, including X-ray crystallography. These ligands have been coordinated to Ni, Pd, and Pt precursors to provide a number of well-characterized group 10 halides. Conversion of these metal halides to metal hydrides was accomplished using borohydride reagents, or by direct interaction of the ligand with the zerovalent metal precursor. The insertion of oxygen into these hydrides in an attempt to prepare metal hydroperoxides has been examined; however, we were unable to obtain stable and isolable hydroperoxide species.     

Development and validation of a reference measurement procedure for certification of phenytoin, phenobarbital, lamotrigine, and topiramate in human serum using isotope-dilution liquid chromatography/tandem mass spectrometry

Phenytoin (PHT), phenobarbital (PHB), lamotrigine (LTG), and topiramate (TPM) are some of the most widely used antiepileptic drugs (AEDs). Monitoring of their concentrations in serum is important for the treatment of epilepsy. A reference measurement procedure (RMP) for certification of PHT, PHB, LTG, and TPM in serum has been developed and critically evaluated. Isotopically labeled compounds of PHT, PHB, LTG, and TPM are used as internal standards for the four AEDs. The four drugs and their respective labeled internal standards are simultaneously extracted from serum using solid-phase extraction prior to reversed-phase liquid chromatography–tandem mass spectrometry (LC-MS/MS). Chromatographic separation was performed using a C₁₈ column. Electrospray ionization (ESI) in the positive ion mode for PHT and LTG, and in the negative ion mode for PHB and TPM were used. The recovery of AEDs added to serum (accuracy of the extraction method) was evaluated by recovery studies of measuring the four drugs in spiked samples with known drug levels. The recoveries of the added drugs ranged from 98.6% to 102.0%. The absolute recoveries (extraction efficiencies) of the four drugs with this method ranged from 97% to 100%. Excellent repeatability was obtained for the four drugs with between-set coefficients of variation (CVs) within 1%. The type B components estimates are conservatively large and are considerably larger than the type A component. Therefore, we use the usual metrological expansion factor of 2 to provide an approximate 95% coverage interval. The relative expanded uncertainties for the four AEDs ranged from 2.3% to 2.4%. This LC-MS/MS RMP for PHT, PHB, LTG, and TPM in serum demonstrating good accuracy and precision can be used to assess the accuracy of routine methods used in clinical laboratories.     

Reaction-driven surface restructuring and selectivity control in allylic alcohol catalytic aerobic oxidation over Pd

Synchronous, time-resolved DRIFTS/MS/XAS cycling studies of the vapor-phase selective aerobic oxidation of crotyl alcohol over nanoparticulate Pd have revealed surface oxide as the desired catalytically active phase, with dynamic, reaction-induced Pd redox processes controlling selective versus combustion pathways.     

SE(R)RS devices fabricated by a laser electrodispersion method

A novel laser electrodispersion (LE) technique was employed to deposit gold nanoparticles onto Si and SiO(x) surfaces. The LE technique combines laser ablation with cascade fission of liquid metal micro-drops, which results in the formation of nanoparticles upon rapid cooling. The shape and the size distribution of the Au nanoparticles prepared by LE depend on the nature of the support. Gold nanoparticles were also deposited in the channels of microreactors fabricated by wet etching of Si and used as SE(R)RS sensors. The influence of the nanoparticle surface density as well as of the nature of the substrate on the Raman response was studied. At an appropriate surface density of the deposited nanoparticles a significant enhancement of Raman signal was observed showing the possibility to create efficient SERS substrates. Application of microfluidic devices in surface enhanced Raman spectroscopy (SERS) in continuous-flow mode with sensor regeneration is described.     

Multicompartment polymer nanostructures with ratiometric dual-emission pH-sensitivity

Pyrazine-labeled multicompartment nanostructures are shown to exhibit enhanced pH-responsive blue-shifted fluorescence emission intensities compared to their simpler core-shell spherical analogs. An amphiphilic linear triblock terpolymer of ethylene oxide, N-acryloxysuccinimide, and styrene, PEO(45)-b-PNAS(105)-b-PS(45), which lacks significant incompatibility for the hydrophobic block segments and undergoes gradual hydrolysis of the NAS units, underwent supramolecular assembly in mixtures of organic solvent and water to afford multicompartment micelles (MCMs) with a narrow size distribution. The assembly process was followed over time and found to evolve from individual polymer nanodroplets containing internally phase segregated domains, of increasing definition, and ultimately to dissociate into discrete micelles. Upon covalent cross-linking of the MCMs with pH-insensitive pyrazine-based diamino cross-linkers, pH-responsive, photonic multicompartment nanostructures (MCNs) were produced. These MCNs exhibited significant enhancement of overall structural stability, in comparison with the MCMs, and internal structural tunability through the cross-linking chemistry. Meanwhile, the complex compartmentalized morphology exerted unique pH-responsive fluorescence dual-emission properties, indicating promise in ratiometric pH-sensing applications.     

Hydrogenolysis of palladium(II) hydroxide, phenoxide, and alkoxide complexes

A series of pincer ((tBu)PCP)Pd(II)-OR complexes ((tBu)PCP = 2,6-bis(CH(2)P(t)Bu(2))C(6)H(3), R = H, CH(3), C(6)H(5), CH(2)C(CH(3))(3), CH(2)CH(2)F, CH(2)CHF(2), CH(2)CF(3)) were synthesized to explore the generality of hydrogenolysis reactions of palladium-oxygen bonds. Hydrogenolysis of the Pd hydroxide complex to generate the Pd hydride complex and water was shown to be inhibited by formation of a water-bridged, hydrogen-bonded Pd(II) hydroxide dimer. The Pd alkoxide and aryloxide complexes exhibited more diverse reactivity. Depending on the characteristics of the -OR ligand (steric bulk, electron-donating ability, and/or the presence of β-hydrogen atoms), hydrogenolysis was complicated by hydrolysis by adventitious water, a lack of reactivity with hydrogen, or a competing dissociative β-hydride abstraction reaction pathway. Full selectivity for hydrogenolysis was observed with the partially fluorinated Pd(II) 2-fluoroethoxide complex. The wide range of Pd-OR substrates examined helps to clarify the variety of reaction pathways available to late-transition-metal alkoxides as well as the conditions necessary to tune the reactivity to hydrogenolysis, hydrolysis, or dissociative β-hydride abstraction.     

Development of proneurogenic, neuroprotective small molecules

Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.     

Aperiodicity in the near field of full-scale rotor blade tip vortices

Blade tip vortices are the dominant vortical structures of the helicopter flow field. The inherent complexity of the vortex dynamics has led to an increasing interest in full-scale in situ experiments, where the near field, closely behind the blade, is of particular interest, since measures of vortex control mostly target this initial stage of development. To examine the near field, three-component particle image velocimetry (PIV) measurements of blade tip vortices of a full-scale helicopter in simulated hover flight in ground effect were conducted. A feasible and robust evaluation procedure was developed to minimise the shortcomings of full-scale PIV applications, such as a moderate spatial resolution and an elevated measurement noise level. At vortex ages ranging from y_v=1^°\psi_{\rm v}=1^{\circ} to 30°, a pronounced aperiodicity and asymmetry of the vortex were observed in -sections perpendicular to the vortex axes. At y_v=1^°\psi_{\rm v}=1^{\circ}, a preferential orientation of the vortex was observed. For increasing wake age, vortex wandering increased while the asymmetry of the vortex cores decreased. The high level of aperiodicity and core asymmetry must be taken into account when considering phase-averaged vortex characteristics in the near wake region.