Vapor-phase polymerization of nanofibrillar poly(3,4-ethylenedioxythiophene) for supercapacitors.

Nanostructures of the conducting polymer poly(3,4-ethylenedioxythiophene) with large surface areas enhance the performance of energy storage devices such as electrochemical supercapacitors. However, until now, high aspect ratio nanofibers of this polymer could only be deposited from the vapor-phase, utilizing extrinsic hard templates such as electrospun nanofibers and anodized aluminum oxide. These routes result in low conductivity and require postsynthetic template removal, conditions that stifle the development of conducting polymer electronics. Here we introduce a simple process that overcomes these drawbacks and results in vertically directed high aspect ratio poly(3,4-ethylenedioxythiophene) nanofibers possessing a high conductivity of 130 S/cm. Nanofibers deposit as a freestanding mechanically robust film that is easily processable into a supercapacitor without using organic binders or conductive additives and is characterized by excellent cycling stability, retaining more than 92% of its initial capacitance after 10,000 charge/discharge cycles. Deposition of nanofibers on a hard carbon fiber paper current collector affords a highly efficient and stable electrode for a supercapacitor exhibiting gravimetric capacitance of 175 F/g and 94% capacitance retention after 1000 cycles.

A new biarylphosphine ligand for the Pd-catalyzed synthesis of diaryl ethers under mild conditions.

A new bulky biarylphosphine ligand (L8) has been developed that allows the Pd-catalyzed C-O cross-coupling of a wide range of aryl halides and phenols under milder conditions than previously possible. A direct correlation between the size of the ligand substituents in the 2', 4', and 6' positions of the nonphosphine containing ring and the reactivity of the derived catalyst system was observed. Specifically, the rate of coupling increased with the size of these substituents.

Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.

Kinetic and equilibrium lithium acidities of arenes: theory and experiment.

Kinetic acidities of arenes, ArH, measured some time ago by hydrogen isotope exchange kinetics with lithium cyclohexylamide (LiCHA) in cyclohexylamine (CHA) show a wide range of reactivities that involve several electronic mechanisms. These experimental reactivities give an excellent Brønsted correlation with equilibrium lithium ion pair acidities (pK(Li)) derived as shown recently from computations of ArLi.2E (E = dimethyl ether). The various electronic mechanisms are well modeled by ab initio HF calculations with modest basis sets. Additional calculations using NH(3) as a model for CHA further characterize the TS of the exchange reactions. The slopes of Brønsted correlations of ion pair systems can vary depending on the nature of the ion pairs.

An efficient process for pd-catalyzed C-N cross-coupling reactions of aryl iodides: insight into controlling factors.

An investigation into Pd-catalyzed C-N cross-coupling reactions of aryl iodides is described. NaI is shown to have a significant inhibitory effect on these processes. By switching to a solvent system in which the iodide byproduct was insoluble, reactions of aryl iodides were accomplished with the same efficiencies as aryl chlorides and bromides. Using catalyst systems based on certain biarylphosphine ligands, aryl iodides were successfully reacted with an array of primary and secondary amines in high yields. Lastly, reactions of heteroarylamines and heteroaryliodides were also conducted in high yields.

Mutation in EGFP domain of LDL receptor-related protein 6 impairs cellular LDL clearance.

Mutation in the EGFP domain of LDL receptor-related protein 6 (LRP6(R611C)) is associated with hypercholesterolemia and early-onset atherosclerosis, but the mechanism by which it causes disease is not known. Cholesterol uptake was examined in cells from LRP6(+/-) mice and LRP6(R611C) mutation carriers. Splenic B cells of LRP6(+/-) mice have significantly lower LRP6 expression and low-density lipoprotein (LDL) uptake than those of the wild-type littermates. Although similar levels of total LRP6 were found in lymphoblastoid cells (LCLs) of LRP6(R611C) mutation carriers and those of the unaffected family member, LDL uptake was significantly lower in the mutant cells. Mutant and wild-type receptors show similar affinities for apolipoprotein B at neutral pH. LRP6 colocalized with LDL and was coimmunoprecipitated with NPC1 (Niemann-Pick disease type C1), an endocytic regulator of LDL trafficking. However, the cellular localization of LRP6 in the mutant cells shifted from cell surface to late endosomes/lysosomes. Plasma membrane expression levels of LRP6(R611C) was lower compared to wild-type receptor and declined to a greater extent in LDL-rich medium. Further examinations revealed lower efficacy of apolipoprotein B dissociation from LRP6(R611C) compared to wild-type receptor at an acidic pH. These studies identify LRP6 as a receptor for LDL endocytosis and imply that R611C mutation results in reduced LRP6 membrane expression and decreased LDL clearance. Based on our findings, we conclude that the increased affinity of the mutant receptor for LDL in acidic pH leads to their impaired dissociation in late endosomes, which compromises their recycling to the plasma membrane.

Sequence variants in SLITRK1 are associated with Tourette's syndrome.

Tourette's syndrome (TS) is a genetically influenced developmental neuropsychiatric disorder characterized by chronic vocal and motor tics. We studied Slit and Trk-like 1 (SLITRK1) as a candidate gene on chromosome 13q31.1 because of its proximity to a de novo chromosomal inversion in a child with TS. Among 174 unrelated probands, we identified a frameshift mutation and two independent occurrences of the identical variant in the binding site for microRNA hsa-miR-189. These variants were absent from 3600 control chromosomes. SLITRK1 mRNA and hsa-miR-189 showed an overlapping expression pattern in brain regions previously implicated in TS. Wild-type SLITRK1, but not the frameshift mutant, enhanced dendritic growth in primary neuronal cultures. Collectively, these findings support the association of rare SLITRK1 sequence variants with TS.

Gold(I)-catalyzed intramolecular acetylenic Schmidt reaction.

Substituted pyrroles were prepared by a gold(I)-catalyzed acetylenic Schmidt reaction of homopropargyl azides. The reaction allows for regiospecific substitution at each position of the pyrrole ring under mild conditions. A mechanism in which azides serve as nucleophiles toward gold(I)-activated alkynes with subsequent gold(I)-aided expulsion of dinitrogen is proposed.

Basicity of some phosphines in THF.

[reaction: see text] The reaction of several phosphines with an acidic indicator gives both ion pairs and free ions. The value obtained for the pKa of tribenzylphosphine is shown to be reasonable by MO computations. An important limitation is demonstrated for the Fuoss equation of dissociation of ion pairs.