A New Lead Identification Strategy: Screening an sp3-rich and Lead-like Compound Library Composed of 7-Azanorbornane Derivatives

Although the advantages of sp³-rich, sterically complicated molecules in drug development have been pointed out, modern screening libraries are filled with planar, sp²-rich components. Compounds that are sp³-rich are difficult to synthesize, and thus we aimed to invent an efficient method to construct sp³-rich libraries. By modifying sp³-rich 7-azanorbornane scaffolds through click chemistry, we efficiently prepared a small set of compounds. These compounds were not only sp³-rich, but also had sufficient “lead-like” properties in view of molecular weights and hydrophobicity. Screening assays of this library provided weak κ opioid receptor agonists and growth hormone secretagogue receptor agonists with high hit rates. These results indicate that the 7-azanorbornane scaffold may be a “privileged structure” for lead identification in drug discovery.     

Strictly Conserved Residues in Euphorbia tirucalli β‐Amyrin Cyclase: Trp612 Stabilizes Transient Cation through Cation–π Interaction and CH–π Interaction of Tyr736 with Leu734 Confers Robust Local Protein Architecture

The functions of Trp612, Leu734, and Tyr736 of Euphorbia tirucalli β‐amyrin synthase were examined. The aliphatic variants (Ala, Val, Met) of Trp612 showed almost no activity, but the aromatic variants exhibited high activities: 12.5 % of the wild‐type activity for the W612H variant, 43 % for W612F, and 63 % for W612Y. That is, the enzymatic activities of the variants increased in proportion to the increase in π‐electron density. Thus, the major function of Trp612 is to stabilize transient cations through a cation–π interaction. The Phe and Tyr variants caused a distorted folding conformation, especially at the E‐ring site, which generated the aberrantly cyclized products germanicol and lupeol. The L734G and L734A variants exhibited significantly decreased activities but yielded taraxerol in a high production ratio. The Val, Ile, and Met variants showed markedly high activities (56–78 % of wild‐type activity); therefore, appropriate steric bulk is required at this position. The aliphatic variants of Tyr736 showed markedly decreased activities, but the Phe mutant exhibited high activity (67 %), which indicates that the π electrons are critical for catalysis. Homology modeling indicated that Tyr736 and Leu734 are perpendicular to the substrate and are situated face to face, which suggests that a CH–π interaction occurs between Tyr736 and Leu734, reinforcing the protein architecture, and that Tyr736 cannot stabilize cationic intermediates through a cation–π interaction.     

Effect of morphology on shear viscosity for binary blends of polycarbonate and polystyrene

The structure and rheological properties of binary blends of polycarbonate (PC) and polystyrene (PS) were investigated using various PS samples with different molecular weights, namely PS1k (M_w = 1,000), PS53k (M_w = 53,000), and PS240k (M_w = 240,000). The blends with PS53k and PS240k show phase-separated structures, whereas the blend with PS1k is miscible. The shear viscosity decreases greatly on addition of PS53k and PS240k, especially at high shear rates, which would be a great advantage at processing operations. Because the nonlinear response occurs in the small strain region for multilayered films of PC and PS240k, the origin of the significant viscosity drop for the phase-separated system is interfacial slippage at the phase boundary.     

Solidification of Al2O3–YAG eutectic composites with off-metastable eutectic composition from undercooled melt produced by melting Al2O3–YAP eutectics

It has been reported that solidification of the Al₂O₃–YAG equilibrium eutectic structure follows melting of the Al₂O₃–YAP metastable eutectic structure. Since the exothermic heat due to solidification was consumed by the endothermic heat due to melting, a fine and uniform eutectic structure was obtained. However, the composition of the Al₂O₃–YAG eutectic structure is restricted to the metastable eutectic composition. In this paper, Al₂O₃–YAG eutectic compacts with an off-metastable eutectic composition were prepared by the addition of Al₂O₃ particles to Al₂O₃–YAP eutectic particles with diameters less than 20 μm. In compositions ranging from 18.5 mol%Y₂O₃ to 13.5 mol%Y₂O₃, dense Al₂O₃–YAG eutectic compacts were formed without any Al₂O₃ segregation. The flexural strength and the fracture toughness remained almost unchanged with the increase in the Al₂O₃ phase. The addition of Al₂O₃ particles to the Al₂O₃–YAP eutectic particles enabled the matrix phase to change from the YAG phase to the Al₂O₃ phase.     

Non‐Enzymatic Geometry‐Selective Acylation of Tri‐ and Tetrasubstituted α,α′‐Alkenediols

A highly geometry‐selective organocatalytic acylation of tri‐ and tetra‐substituted 2‐alkylidene‐1,3‐propanediols has been developed. The highly E‐selective acylation of various tetrasubstituted 2‐alkylidene‐1,3‐propanediols was achieved in 96 to >99% selectivity for the first time by a non‐enzymatic protocol.     

A Novel KCaNi/α-Al2O3 Catalyst for CH4 Reforming with CO2

A potassium and calcium co-promoted nickel catalyst (KCaNi/-Al₂O₃) prepared by a direct impregnation method possessed a high activity, high stability and excellent coke resistance properties in CH₄ reforming with CO₂. XRD, XPS and H₂-TPR characterizations indicated that (i) Ca and K strengthened the interaction between Ni and -Al₂O₃ and promoted the formation of a unique NiAl₂O₄ phase on the surface of the catalyst and (ii) Ca and K increased the dispersion of Ni and retarded its sintering. Coking reactions (CH₄ temperature-programmed decomposition and O₂-TPO) disclosed that K reduced carbon formation via CH₄ decomposition.     

Investigation of CH4 Reforming with CO2 on Meso-Porous Al2O3-Supported Ni Catalyst

Meso-porous Al₂O₃-supported Ni catalysts exhibited the highest activity, stability and excellent coke-resistance ability for CH₄ reforming with CO₂ among several oxide-supported Ni catalysts (meso-porous Al₂O₃ (Yas1-2, Yas3-8), -Al₂O₃, -Al₂O₃, SiO₂, MgO, La₂O₃, CeO₂ and ZrO₂). The properties of deposited carbons depended on the properties of the supports, and on the meso-porous Al₂O₃-supported Ni catalyst, only the intermediate carbon of the reforming reaction formed. XRD and H₂-TPR analysis found that mainly spinel NiAl₂O₄ formed in meso-porous Al₂O₃ and -Al₂O₃-supported catalysts, while only NiO was detected in -Al₂O₃, SiO₂, CeO₂, La₂O₃ and ZrO₂ supports. The strong interaction between Ni and meso-porous Al₂O₃ improved the dispersion of Ni, retarded its sintering and improved the activated adsorption of CO₂. The coking reaction via CH₄ temperature-programed decomposition indicated that meso-porous Al₂O₃-supported Ni catalysts were less active for carbon formation by CH₄ decomposition than Ni/-Al₂O₃ and Ni/-Al₂O₃.     

Syntheses of Spinon Thermal Conductivity Materials in Sr–Cu–O System by Glass‐Ceramics Technique

We have synthesized spinon thermal conductivity materials in Sr–Cu–O system by glass‐ceramics technique. The materials are promising for active control of thermal energy in microelectronic devices because of high and anisotropic thermal conduction, its controllability, and electric insulation. Nevertheless, research on these materials has been limited to that concerning theoretical perspectives and investigation of physical properties using large single crystals. In this study, we adopt glass‐ceramics technique to synthesize these materials: We prepared melt‐quenched multicomponent oxides including SrO and CuO, and checked its glass‐forming ability and crystallization behaviors by heating. As a result, we have found that SrCuO₂ and Sr₁₄Cu₂₄O₄₁, known as the spinon thermal conductivity materials, are synthesized using SrO–CuO–?Li₂O–?Al₂O₃?–Ga₂O₃ system. This synthesis process for the system will provide practical application of the spinon thermal conductivity materials.     

Hydrogen‐bonding interaction between poly(ε‐caprolactone) and low‐molecular‐weight amino compounds

The specific interactions between several low‐molecular‐weight diamino compounds and poly(ε‐caprolactone) (PCL) have been investigated by FT‐IR. It was found that PCL and 3,3′‐diaminodiphenylmethane (3,3′‐DADPM) interact through strong intermolecular hydrogen bonds in the blend. Thermal and mechanical properties of PCL/3,3′‐DADPM blends were investigated by DSC and tensile measurements, respectively. The glass transition temperature of the blend increases while both the melting point and the elongation‐at‐break of the blend decrease with the increase of 3,3′‐DADPM content. Besides 3,3′‐DADPM, several other low‐molecular‐weight compounds containing two amino groups, such as o‐phenylenediamine or 1,6‐diaminohexane, were also added into PCL and the corresponding blend systems were investigated by FT‐IR and DSC. The effect of the chemical structure of the additives on the properties of PCL is discussed. © 2001 Society of Chemical Industry