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.     

Measurement of self-diffusion coefficients in Li ionic conductors by using the short-lived radiotracer of 8Li

For the effective use of short-lived radioactive beams, soon to be available at the Tokai Radioactive Ion Accelerator Complex, the authors have developed a radiotracer method for diffusion studies in solids. The experimental test was performed by the measurement of the diffusion coefficients of Li in a sample of the compound βLiAl using an α-emitting radiotracer of ⁸Li (T_1/2=0.84 s). It was found that the time-dependent yields of the α particles from the diffusing ⁸Li that was initially implanted in the sample could be used as a measure of the diffusivity of the tracer in a nondestructive way. The method was applied to measure the self-diffusion coefficients of Li in βLiGa, and for investigating how the Li diffusion in the Li ionic conductors is affected by the concentration of atomic defects (i.e., the existence of the atomic vacancies of Li and the defects in Ga sites that are replaced by Li).     

Room temperature aging behavior of Ti-Nb-Mo-based superelastic alloys

The effect of room temperature (RT) aging on the superelasticity of Ti-Nb-Mo-based superelastic alloys is investigated. The results show that annealing at relatively low temperatures such as 973 K after severe cold rolling results in poor resistance to the effect of RT aging. The transformation stress increases considerably due to the formation of an isothermal ω phase at RT. Addition of Sn is partially effective in suppressing the RT aging effect in the specimens annealed at 973 K. The RT aging effect is suppressed by increasing the annealing temperature, due to the annihilation of lattice defects or non-equilibrium vacancies introduced during cold rolling, which are responsible for accelerating the diffusion process, however, superelasticity is reduced by annealing at higher temperatures, due to a decrease in the critical stress for slip deformation (σ_CSS). The specimen annealed at 1173 K followed by aging at 773 K exhibits stable superelasticity with a high resistance to the effect of RT aging. Annealing at 1173 K causes the annihilation of lattice defects or non-equilibrium vacancies, while aging at 773 K induces precipitation of the α phase, which in turn causes an increase in σ_CSS, and further enhances the resistance to the RT aging effect by enriching the matrix with β-stabilizing elements.     

In situ X-ray diffraction of surface oxide on type 430 stainless steel in breakaway condition using synchrotron radiation

Changes in the crystal structure of type 430 stainless steel and the oxides on its surface were studied in situ at 1373 K using a high-intensity synchrotron X-ray source provided by SPring-8 in Japan. The surface of the steel was initially covered with Cr₂O₃, which was then converted to FeCr₂O₄, and finally Fe₃O₄ and Fe₂O₃ formed on it. These results indicated that the reason for the breakaway oxidation in type 430 stainless steel is Cr depletion beneath Cr₂O₃ layer and the subsequent ionisation of Fe, not the simple mechanical failure of Cr₂O₃.     

Atom probe tomography of nanoscale microstructures within precipitate free zones in Al–Zn–Mg(–Ag) alloys

Solute distributions in the vicinity of grain boundaries in Al–Zn–Mg(–Ag) alloys were studied using a three-dimensional atom probe, in order to elucidate the mechanism of formation of precipitate free zones (PFZs) and the fundamental role of Ag in controlling PFZ width. It is shown that nanoscale clusters are formed within the PFZ in Al–Zn–Mg, despite the solute concentration remaining at the levels in the as-quenched state. Such observations have not previously been possible, and show unambiguously that vacancy depletion is the dominant mechanism of formation of PFZs in this alloy. In the Ag-containing alloy, a narrower PFZ is observed, with a reduced solute level, showing that here the dominant mechanism of PFZ formation is solute depletion. The role of Ag in this change of mechanism appears to be due to its favorable interactions not only with Mg and Zn atoms but also with vacancies.     

Kinetics of Enthalpy Relaxation at the Glass Transition in Ternary Tellurite Glasses

The kinetics of enthalpy relaxation (recovery) at the glass transition in x K₂O·(20− x )MgO·80TeO₂ glasses has been examined from heat capacity measurements using differential scanning calorimetry to clarify the features of the structural relaxation in ternary TeO₂-based glasses. Ternary glasses such as 10K₂O·10MgO·80TeO₂ show high thermal resistance against crystallization compared with binary glasses. The degree of fragility m estimated from the activation energy for viscous flow E _η and the glass transition temperature T _g is m = 55–62, indicating a fragile character in TeO₂-based glasses. Large heat capacity changes of 43.1–48.2 J·mol⁻¹·K⁻¹ are also observed at the glass transition. The activation energy for enthalpy relaxation Δ H is evaluated from the cooling rate dependence of the limiting fictive temperature, and values of Δ H = 897–1268 kJ·mol⁻¹ are obtained. Negative deviation from additivity in Δ H is also observed. Values of the Kovacs–Aklonis–Huchinson–Ramos (KAHR) parameter θ estimated from Δ H and T _g are 0.33–0.42 K⁻¹. It has been proposed that ternary glasses have more homogeneous and constrained glass structure compared with binary glasses.     

Poly(pyridine-2,5-diyl)–CuCl2 catalyst for synthesis of dimethyl carbonate by oxidative carbonylation of methanol: catalytic activity and corrosion influence

A -conjugated polymer, poly(pyridine-2,5-diyl) (PPy) was investigated as a support for CuCl₂ in the synthesis of dimethyl carbonate by oxidative carbonylation of methanol. The PPy–CuCl₂ adduct had high catalytic activity which was comparable to that of the homogeneous CuCl₂ catalyst. The adduct caused corrosion of stainless-steel vessels only to minor extent, compared with the homogeneous CuCl₂ catalyst. This PPy–CuCl₂ catalyst was easily recycled by filtration and showed a similar catalytic activity in the third time use. The presence of the -conjugated system in PPy, through which electrons can move, may bring about the high catalytic activity for the oxidative carbonylation of methanol, which involves Cu(II)/Cu(I) redox processes.     

Effect of medium-chain fatty acid positional distribution in dietary triacylglycerol on lymphatic lipid transport and chylomicron composition in rats

The present study was carried out to examine if the positional distribution of medium-chain fatty acid (MCF) in dietary synthetic fat influences lymphatic transport of dietary fat and the chemical composition of chylomicrons in rats with permanent cannulation of thoracic duct. Four types of synthetic triacylglycerol were prepared: (i) sn-1(3) MCF-sn 2 linoleic acid, (ii) interesterified sn-1(3) MCF-sn 2 linoleic acid, (iii) sn-2 MCF-sn-1(3) linoleic acid, and (iv) interesterified sn-2 MCF-sn-1(3) linoleic acid. A purified diet composed of equal amounts of the synthetic fat and cocoa butter was given to rats with permanent lymph duct cannulation. The positional distribution of MCF in the dietary fat had no significant effect on the lymph flow, triacylglycerol output, phospholipid output, lipid composition of chylomicrons, or the particle size. The positional distribution of MCF in the synthetic triacylglycerol was maintained in the chylomicron triacylglycerol. These results showed that MCF in the dietary triacylglycerol is transported into lymphatics and the positional distribution is well preserved in chylomicron triacylglycerol.     

Improvement in mechanical properties of poly(p‐phenylene sulfide) fibers by high‐tension multiannealing method

High‐tension multiannealing (HTMA) was applied to improve the tensile properties of poly(p‐phenylene sulfide) fibers, which was furthermore applied to the fibers produced and improved with the zone‐drawing and zone‐annealing treatments. The HTMA treatment was repeatedly applied to the fibers under the conditions of a 250°C temperature and an applied tension of between 201.0 and 188.0 MPa. As a result, at the 13th treatment the degree of crystallinity increased to 40%. On the other hand, the orientation factor of crystallites increased dramatically to 0.982 during the zone‐drawing treatment, but increased only slightly during the subsequent treatments of zone annealing and HTMA. The finally obtained fiber had a tensile modulus of 10.4 GPa and a tensile strength of 0.73 GPa. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 75: 1569–1576, 2000