Gel-induced selective crystallization of polymorphs

Although nanoporous materials have been explored for controlling crystallization of polymorphs in recent years, polymorphism in confined environments is still poorly understood, particularly from a kinetic perspective, and the role of the local structure of the substrate has largely been neglected. Herein, we report the use of a novel material, polymer microgels with tunable microstructure, for controlling polymorph crystallization from solution and for investigating systematically the effects of nanoconfinement and interfacial interactions on polymorphic outcomes. We show that the polymer microgels can improve polymorph selectivity significantly. The polymorphic outcomes correlate strongly with the gel-induced nucleation kinetics and are very sensitive to both the polymer microstructure and the chemical composition. Further mechanistic investigations suggest that the nucleation-templating effect and the spatial confinement imposed by the polymer network may be central to achieving polymorph selectivity. We demonstrate polymer microgels as promising materials for controlling crystal polymorphism. Moreover, our results help advance the fundamental understanding of polymorph crystallization at complex interfaces, particularly in confined environments.     

Preparation of azulene-derived fulvenedialdehydes and their application to the synthesis of stable adj-dicarbaporphyrinoids

A "2 + 2" strategy for synthesizing adj-dicarbaporphyrinoid systems has been developed. In a model study, an azulenylmethylpyrrole dialdehyde was condensed with a dipyrrylmethane in the presence of HCl, followed by oxidation with ferric chloride, to give a modest yield of an azuliporphyrin. Fulvene aldehydes were prepared by reacting an indene-derived enamine with azulene aldehydes in the presence of Bu(2)BOTf, and azulene dialdehydes similarly reacted to give fulvene dialdehydes. The dialdehydes were condensed with dipyrrylmethanes in TFA/dichloromethane to afford good to excellent yields of dicarbaporphyrinoids with adjacent indene and azulene subunits. These 22-carbaazuliporphyrins exhibited significant diatropic character, and this property was magnified upon protonation. These characteristics are attributed to tropylium-containing resonance contributors that possess 18π electron delocalization pathways. Protonation studies demonstrated that C-protonation readily occurred at the interior indene carbon, but deuterium exchange also occurred at the internal azulene CH as well as at the meso-positions with TFA-d. Reaction of a carbaazuliporphyrin with silver(I) acetate in methanol or ethanol solutions also gave unusual nonaromatic dialkoxy derivatives.     

Characterization of the 1st and 2nd EF-hands of NADPH oxidase 5 by fluorescence, isothermal titration calorimetry, and circular dichroism

Background

Superoxide generated by non-phagocytic NADPH oxidases (NOXs) is of growing importance for physiology and pathobiology. The calcium binding domain (CaBD) of NOX5 contains four EF-hands, each binding one calcium ion. To better understand the metal binding properties of the 1^st and 2^nd EF-hands, we characterized the N-terminal half of CaBD (NCaBD) and its calcium-binding knockout mutants.

Results

The isothermal titration calorimetry measurement for NCaBD reveals that the calcium binding of two EF-hands are loosely associated with each other and can be treated as independent binding events. However, the Ca²⁺ binding studies on NCaBD(E31Q) and NCaBD(E63Q) showed their binding constants to be 6.5 × 10⁵ and 5.0 × 10² M^-1 with ??Hs of -14 and -4 kJ/mol, respectively, suggesting that intrinsic calcium binding for the 1^st non-canonical EF-hand is largely enhanced by the binding of Ca²⁺ to the 2^nd canonical EF-hand. The fluorescence quenching and CD spectra support a conformational change upon Ca²⁺ binding, which changes Trp residues toward a more non-polar and exposed environment and also increases its ??-helix secondary structure content. All measurements exclude Mg²⁺-binding in NCaBD.

Conclusions

We demonstrated that the 1^st non-canonical EF-hand of NOX5 has very weak Ca²⁺ binding affinity compared with the 2^nd canonical EF-hand. Both EF-hands interact with each other in a cooperative manner to enhance their Ca²⁺ binding affinity. Our characterization reveals that the two EF-hands in the N-terminal NOX5 are Ca²⁺ specific.

Graphical abstract

     

Exponential distance dependence of photoinitiated stepwise electron transfer in donor-bridge-acceptor molecules: implications for wirelike behavior

Donor-bridge-acceptor (D-B-A) systems in which a 3,5-dimethyl-4-(9-anthracenyl)julolidine (DMJ-An) chromophore and a naphthalene-1,8:4,5-bis(dicarboximide) (NI) acceptor are linked by oligomeric 2,7-fluorenone (FN(n)) bridges (n = 1-3) have been synthesized. Selective photoexcitation of DMJ-An quantitatively produces DMJ(+?)-An(-?), and An(-?) acts as a high-potential electron donor. Femtosecond transient absorption spectroscopy in the visible and mid-IR regions showed that electron transfer occurs quantitatively in the sequence: DMJ(+?)-An(-?)-FN(n)-NI → DMJ(+?)-An-FN(n)(-?)-NI → DMJ(+?)-An-FN(n)-NI(-?). The charge-shift reaction from An(-?) to NI(-?) exhibits an exponential distance dependence in the nonpolar solvent toluene with an attenuation factor (β) of 0.34 ?(-1), which would normally be attributed to electron tunneling by the superexchange mechanism. However, the FN(n)(-?) radical anion was directly observed spectroscopically as an intermediate in the charge-separation mechanism, thereby demonstrating conclusively that the overall charge separation involves the incoherent hopping (stepwise) mechanism. Kinetic modeling of the data showed that the observed exponential distance dependence is largely due to electron injection onto the first FN unit followed by charge hopping between the FN units of the bridge biased by the distance-dependent electrostatic attraction of the two charges in D(+?)-B(-?)-A. This work shows that wirelike behavior does not necessarily result from building a stepwise, energetically downhill redox gradient into a D-B-A molecule.     

A robust small-molecule microarray platform for screening cell lysates

Herein we report the expanded functional group compatibility of small-molecule microarrays to include immobilization of primary alcohols, secondary alcohols, phenols, carboxylic acids, hydroxamic acids, thiols, and amines on a single slide surface. Small-molecule "diversity microarrays" containing nearly 10,000 known bioactive small molecules, natural products, and small molecules originating from several diversity-oriented syntheses were produced by using an isocyanate-mediated covalent capture strategy. Selected printed bioactive compounds were detected with antibodies against compounds of interest. The new surface of the diversity microarrays is highly compatible with approaches involving cellular lysates. This feature has enabled a robust, optimized screening methodology using cellular lysates, allowing the detection of specific interactions with a broad range of binding affinity by using epitope-tagged or chimeric fluorescent proteins without prior purification. We believe that this expanded research capability has considerable promise in biology and medicine.     

Rapid assessment of mid-infrared refractive index anisotropy using a prism coupler: chemical vapor deposited ZnS

A state-of-the-art mid-infrared prism coupler was used to study suspected anisotropy in the refractive index of forward-looking-infrared grade chemical vapor deposited (CVD) zinc sulfide. Samples were prepared with columnar grain structure in and perpendicular to the sample plane, as well as from different depths in the CVD growth body. This study was motivated by the growing industry concern among optical design engineers, as well as developers of mid-infrared systems, over the reliability of historically accepted index data. Prior photoluminescence and x-ray diffraction measurements have suggested that refractive index may vary according to sample orientation with respect to the grain structure. Measurements were conducted to provide optical dispersion and thermal index (dn/dT) data at discrete laser wavelengths between 0.633 and 10.591 μm at two temperature set points (30 °C and 90 °C). Refractive index measurements between samples exhibited an average standard deviation comparable to the uncertainty of the prism coupler measurement (0.0004 refractive index units), suggesting that the variation in refractive index as a function of sample orientation and CVD deposition time is negligible and should have no impact on subsequent optical designs. Measured dispersion data at mid-infrared wavelengths were also found to agree well with prior published measurements.     

Synthesis of peptidomimetics, δ- and {\varepsilon}-lactam tetrazoles

A concise two-step procedure for the synthesis of novel δ-lactam tetrazoles has been established via the Ugi-azide reaction using 5-oxohexanoic acid along with primary amines, isocyanides, and azidotrimethylsilane followed by 1,1'-carbonyldiimidazole-mediated intramolecular amide formation. Expansion to [Formula: see text]-lactam tetrazole scaffolds was accomplished using methyl 6-oxoheptanoate via the same Ugi-azide reaction followed by basic hydrolysis and SOCl(2) activation to enable lactam formation.     

High‐Output Polymer Screening: Exploiting Combinatorial Chemistry and Data Mining Tools in Catalyst and Polymer Development

High‐output polymer screening (HOPS) combines automated polymerization with online reaction monitoring, rapid polymer characterization and novel fingerprint technology useful in polymer preparation as well as polymer processing and polymer additive development. Originally, HOPS was introduced to develop polymerization catalysts and polyolefin materials more effectively. In comparison to conventional high‐throughput screening, focusing on ultrahigh speed of catalyst screening using arrays of miniaturized reactors, output‐oriented, process‐relevant HOPS is aiming at generating and exploiting high information density (useful information/experiment). Catalyst systems for olefin polymerization are evaluated in automated workstations with multiparallel as well as semi‐ and fully automated, upgraded lab reactors. Automated polymerizations under standardized conditions afford large families of well‐characterized polymers which serve as calibration samples for data analysis. Data analysis, using multivariate calibration, is the key to basic correlations between spectroscopic information and catalyst and polymer properties as well as reaction parameters and processing conditions. IR spectroscopic fingerprints are used to measure chemical copolymer composition, density, molecular weight as well as thermal and even mechanical properties. This fingerprint technology can be applied in online quality control and facilitates transfer from lab results into pilot and production plants. Fingerprint methods are important components of rapid online analysis and can reduce the need for time‐ and money‐consuming polymer testing.

Fingerprint technology combines spectroscopic analysis by means of “cheap” spectrometers with multivariate calibration.     

AGSE: A Novel Grape Seed Extract Enriched for PP2A Activating Flavonoids That Combats Oxidative Stress and Promotes Skin Health

Environmental stimuli attack the skin daily resulting in the generation of reactive oxygen species (ROS) and inflammation. One pathway that regulates oxidative stress in skin involves Protein Phosphatase 2A (PP2A), a phosphatase which has been previously linked to Alzheimer’s Disease and aging. Oxidative stress decreases PP2A methylation in normal human dermal fibroblasts (NHDFs). Thus, we hypothesize agents that increase PP2A methylation and activity will promote skin health and combat aging. To discover novel inhibitors of PP2A demethylation activity, we screened a library of 32 natural botanical extracts. We discovered Grape Seed Extract (GSE), which has previously been reported to have several benefits for skin, to be the most potent PP2A demethylating extract. Via several fractionation and extraction steps we developed a novel grape seed extract called Activated Grape Seed Extract (AGSE), which is enriched for PP2A activating flavonoids that increase potency in preventing PP2A demethylation when compared to commercial GSE. We then determined that 1% AGSE and 1% commercial GSE exhibit distinct gene expression profiles when topically applied to a 3D human skin model. To begin to characterize AGSE’s activity, we investigated its antioxidant potential and demonstrate it reduces ROS levels in NHDFs and cell-free assays equal to or better than Vitamin C and E. Moreover, AGSE shows anti-inflammatory properties, dose-dependently inhibiting UVA, UVB and chemical-induced inflammation. These results demonstrate AGSE is a novel, multi-functional extract that modulates methylation levels of PP2A and supports the hypothesis of PP2A as a master regulator for oxidative stress signaling and aging in skin.