(R/S)‐BINOL‐α‐Phosphoryloxy Enecarbamate‐Mediated and (R/S)‐Titanium(IV) BINOLates‐Catalyzed Enantioselective Intramolecular Heck/Aza‐Diels–Alder Cycloaddition (IHADA): An Expedient Methodology

An (R/S)‐titanium(IV) BINOLate‐catalyzed highly enantioselective intramolecular Heck/aza‐Diels–Alder cycloaddition (IHADA) cascade was developed to prepare tetrahydropyridoindoles (tHPs) and octahydropyrazinopyridoindoles (oHPPs) from in situ generated (R/S)‐BINOL α‐phosphoryloxy carbamate ( αPPC2 ) in one pot. Chiral cooperativity between (R/S)‐αPPC2 and (R/S)‐titanium(IV) BINOLate was observed and successfully utilized for the construction of various tHPs (7 examples) and oHPPs (17 examples).

     

1-[2-(1-Cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one: a Histamine H3 Receptor Inverse Agonist with Efficacy in Animal Models of Cognition

A series of chemical optimizations, which was guided by in vitro affinity at histamine H₃ receptor (H₃R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]propan-1-one ( 45 e ) as a potent and selective (K_i=4.0 nM) H₃R inverse agonist. Dipsogenia induced by (R)-α-methylhistamine was dose dependently antagonized by 45 e , confirming its functional antagonism at H₃R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half-life in both rats and dogs. It has demonstrated high receptor occupancy (ED₈₀=0.22 mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub-therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, in vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.     

Structure-function studies of an engineered scaffold protein derived from Stefin A. II: Development and applications of the SQT variant

Constrained binding peptides (peptide aptamers) may serve as tools to explore protein conformations and disrupt protein-protein interactions. The quality of the protein scaffold, by which the binding peptide is constrained and presented, is of crucial importance. SQT (Stefin A Quadruple Mutant-Tracy) is our most recent development in the Stefin A-derived scaffold series. Stefin A naturally uses three surfaces to interact with its targets. SQT tolerates peptide insertions at all three positions. Peptide aptamers in the SQT scaffold can be expressed in bacterial, yeast and human cells, and displayed as a fusion to truncated pIII on phage. Peptides that bind to CDK2 can show improved binding in protein microarrays when presented by the SQT scaffold. Yeast two-hybrid libraries have been screened for binders to the POZ domain of BCL-6 and to a peptide derived from PBP2', specific to methicillin-resistant Staphylococcus aureus. Presentation of the Noxa BH3 helix by SQT allows specific interaction with Mcl-1 in human cells. Together, our results show that Stefin A-derived scaffolds, including SQT, can be used for a variety of applications in cellular and molecular biology. We will henceforth refer to Stefin A-derived engineered proteins as Scannins.     

Porous composites of hydroxyapatite‐filled poly[ethylene‐co‐(vinyl acetate)] for tissue engineering

A novel porous composite of hydroxyapatite/poly[ethylene‐co‐vinyl acetate)] (HAP/EVA) having better osteointegration was fabricated by gas foaming technique using a non toxic gas blowing agent intended for bone replacement applications. Combined techniques of scanning electronic microscopy (SEM) and X‐ray microcomputed tomography (µCT) analysis showed that the pore size and pore volume of the porous composite decrease with the increase of HAP content. The gravimetric analysis evidenced for good pore interconnectivity within the porous composites. Energy dispersive X‐ray analysis (EDX) studies inveterated the even scattering of Ca ions which in turn indicate the uniform dispersion of HAP particles in the composites. The significant gradation in Ca ion concentration seen in EDX studies is well accordance with the amount of HAP loading in the sample. Mechanical properties of the porous composite having different HAP content were measured to have the compressive strength varying from 1.06 to 2.2 MPa. Non‐cytotoxic character of the material was observed by the cytocompatibility studies. The metabolic activity of L929 cells seeded on the material assessed by [3‐(4,5‐dimethylthiazol)‐2‐yl]‐2,5‐diphenyltertrazolium bromide (MTT) assay was found to be 91.8%. The adhesion and migration of the cells inside the pore walls were visualized by confocal microscopy. Copyright © 2010 Society of Chemical Industry     

Measurement of intrinsic rates for homogeneous gas‐phase reactions at high temperatures

A coiled quartz tubular reactor has been designed to measure the intrinsic reaction kinetics for homogeneous reactions at high temperatures up to 1100°C. Actual gas residence times were less than 100 ms. A simple and well‐studied test reaction (i.e., the decomposition of nitrous oxide, N₂O), with published intrinsic kinetics, was used to verify the operation of the experimental reactor. For this system, Peclet numbers (Pe = uL/DL) computed from experimental conversion data were greater than 1000, indicating that the plug flow assumption could be used with this reactor system to determine intrinsic rate expressions with errors of less than 5% for the conditions studied.     

Thermoplastic elastomeric composition based on maleic anhydride–grafted ground rubber tire

Ground rubber tire (GRT) powder was maleated in an internal mixer using maleic anhydride and dicumyl peroxide at 160°C. Maleated GRT was characterized by using X‐ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, wettability, and differential scanning calorimetry. The physical properties of the dynamically vulcanized 60 : 40, rubber : plastic composition based on acrylated high‐density polyethylene as the plastic phase and ethylene propylene diene rubber containing maleated GRT as the rubber phase were found to be greater than the corresponding composition containing nonmaleated GRT. The blend was found to be reprocessable, like themoplastic elastomers. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 370–378, 2002; DOI 10.1002/app.10348     

Efficient catalytic epoxidation of olefins with hierarchical mesoporous TS-1 using TBHP as an oxidant

A series of hierarchical mesoporous TS-1 zeolites with MFI structure were successfully synthesized via hydrothermal route using amphiphilic organosilanes as pore directing templates. These materials were characterized by nitrogen sorption (for surface area, pore volume and pore size distribution), FTIR, SEM and UV–Visible spectroscopy. These materials are efficient catalysts for liquid phase epoxidation of olefins using TBHP as the oxidant. All these TS-1 samples oxidized cyclohexene selectively into epoxide. For the TS-1 sample with 4.4 % Ti complete conversion of cyclohexene into epoxide was observed.     

Nano boron nitride laminated poly(ethyl methacrylate)/poly(vinyl alcohol) composite films imprinted with silver nanoparticles as gas barrier and bacteria resistant packaging materials

Herein, nano boron nitride (BN) laminated poly(ethyl methacrylate) (PEMA)/poly(vinyl alcohol) (PVA) nanocomposite films are fabricated by using a simple in situ polymerization technique with incorporation of silver nanoparticles (Ag NPs). Structural investigations of PEMA/PVA/Ag@BN nanocomposite thin films are carried out by Fourier-transform infrared spectroscopy, dynamic light scattering, X-ray diffraction analysis, ¹H nuclear magnetic resonance, ¹³C nuclear magnetic resonance, and mass spectrometry. The change in morphology of PEMA/PVA matrix due to the reinforcement of BN platelets are identified by electron microscopic studies. The unique tortuous paths are achieved by the dispersion of BN platelets by which gas penetration is restricted with enhancing the barrier properties of the material by 6.5 folds at 5 wt% BN content as compared with neat PEMA/PVA. Acid and alkali resistant along with biodegradability behavior of as-synthesized nanocomposites are studied. From limiting oxygen index (LOI) results, it is found that the prepared materials are fire retardant in nature owing to effective reinforcement of BN layers. Antibacterial activities of PEMA/PVA/Ag@BN nanocomposite are studied by Xanthomonas citri or axonopodis pv. Citri, Escherichia coli, and Xanthomonas oryzae pv. Oryzae because of Ag NPs reinforcement. The substantial improvements in gas barrier, fire retardant, and antibacterial properties enable the materials for packaging application.     

Anisotropy in mechanical and dynamic properties of composites based on carbon fiber filled thermoplastic elastomeric blends of natural rubber and high density polyethylene

The effects of short carbon fibers on static and dynamic properties of thermoplastic elastomeric blends of natural rubber (NR) and high density polyethylene (HDPE) have been studied. Both mechanical and dynamic properties are dependent on fiber concentration. The fiber aspect ratio ranges from 20 to 30. Adhesion between fiber and matrix is evident from the SEM photomicrographs of the failed composites and from variation of relative damping properties. Fiber orientation occurring during processing causes anisotropy in the physical properties. In composites with longitudinally oriented fibers, tensile failure occurs by both fiber pullout and breakage, while in composites with transversely oriented fibers, matrix failure dominates. The incorporation of fibers into the matrix lowers the tan δ_max value, but no change in glass transition temperature is observed.     

Selective oxidation of alcohols by combinatorial catalysis

High-throughput synthesis and screening of polyoxometalate (POM) and supported-metal libraries have been developed for the selective aerobic oxidation of alcohols to the corresponding aldehydes/ketones in the liquid phase. Libraries consisting of 96 catalysts were prepared in multi-well reactors and screened for catalytic activity using TLC, GC and NMR detection methods. Promising hits identified in the high-throughput primary screens were successfully scaled up and optimized in conventional laboratory test units. Isolated yields confirm high selectivities of more than 90% with quantitative conversions. Substrates tested include primary and secondary alcohols. Specific results will be presented for hydroxymethyl-substituted heterocycles and bicyclo-octanols.