Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine

The histone methyltransferase SET7/9 methylates not only histone but also non‐histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2‐hydroxy group showed the most potent activity. On the other hand, a 3‐hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2‐hydroxycyproheptadine. These results are expected to be helpful for further structure‐based development of SET7/9 inhibitors.     

Engineering of Lipid Nanoparticles by the Multifunctionalization of the Surface with Amino Acid Derivatives for the Neutralization of a Target Toxic Peptide

Protein affinity reagents (e.g., antibodies) are often used for basic research, diagnostics, separations, and disease therapy. Although a lot of “synthetic” protein affinity reagents have been developed as a cost-effective alternative to antibodies, their low biocompatibility is a considerable problem for clinical application. Lipid nanoparticles (LNP) represent a highly biocompatible drug delivery agent. However, little has been reported that LNP itself works as a protein affinity reagent in living animals. Here, LNP is engineered for binding to and neutralizing a target toxic peptide in living animals by multifunctionalization with amino acid derivatives. Multifunctionalized LNP (MF-LNP) is prepared using amino acid derivative-conjugated lipids. Optimized MF-LNP exhibits nanomolar affinity to the target toxic peptide and inhibits toxic peptide-dependent hemolysis and cytotoxicity. In addition, MF-LNP captures and neutralizes the toxic peptide after intravenous injection in the bloodstream; in addition, MF-LNP does not release the toxic peptide in the accumulated organ. These results reveal the potential of using LNP as a highly biocompatible protein affinity reagent such as an antidote.     

Tomakomai Large Scale Crude Oil Fire Experiments

This paper summarizes the results of large-scale crude oil fire experiments conducted in Tomakomai, Japan, in 1998 to obtain information that could be applied to the development of firefighting strategies for, and the design of, huge petroleum storages. Arabian light-equivalent crude oil was burned in pans 5-, 10-, and 20-m in diameter. Most of the experiments were performed under favorable conditions. Measured data include external radiation, infrared image of the flame, flame temperature, gas concentration inside the flame, and other burning characteristics. The height of the strongest radiant emittance was H/D=0.1 to 0.2, where D=pan diameter and H=height from the initial fuel surface, and a kind of fireball appeared occasionally at the intermittant flame zone. Emitted smoke particles were sampled on the ground and observed with a scanning electron micrograph, and the distribution of the diameters of primary smoke particles was examined. The average diameter of primary smoke particles is 53.0 (±10.5)nm. The dependence of burning characteristics and flame structure on pan diameter is discussed. The flame height of the 20-m diameter pan fire is 1.9 (±0.3) D. The burning rate increases as the pan diameters increase, but the radiative fraction decreases as pan diameter increases.     

Effect of Ga2O3 on Sintering and Phase Stability of Sc2O3‐Doped Tetragonal Zirconia Prepared via Aqueous Solution Route

The effects of the presence of Ga₂O₃ on low‐temperature sintering and the phase stability of 4, 5, and 6 mol% Sc₂O₃‐doped tetragonal zirconia ceramics (4ScSZ, 5ScSZ, and 6ScSZ, respectively) were investigated. A series of zirconia sintered bodies with compositions (ZrO₂)_0.99?x(Sc₂O₃)_x(Ga₂O₃)_0.01, x = 0.04, 0.05, and 0.06 was fabricated by sintering at 1000°C to 1500°C for 1 h using fine powders that were prepared via the combination of homogeneous precipitation method and hydrolysis technique using monoclinic zirconia sols synthesized through the forced hydrolysis of an aqueous solution of zirconium oxychloride at 100°C for 168 h. The presence of 1 mol% Ga₂O₃ was effective in reducing sintering temperature necessary to fabricate dense bodies and enabled to obtain dense sintered bodies via sintering at 1100°C for 1 h. The phase stability, that is, low‐temperature degradation behavior of the resultant zirconia ceramics was determined under hydrothermal condition. The zirconia ceramics codoped with 1 mol% Ga₂O₃ and 6 mol% Sc₂O₃ (1Ga6ScZ) fabricated via sintering at 1300°C for 1 h showed high phase stability without the appearance of monoclinic zirconia phase, that is the tetragonal‐to‐monoclinic phase transformation was not observed in the 1Ga6ScZ after treatment under hydrothermal condition at 150°C for 30 h.     

Syndiotactic‐specific radical polymerization of N‐isopropylacrylamide in toluene at low temperatures in the presence of silyl alcohols

The radical polymerization of N‐isopropylacrylamide was carried out in toluene at low temperatures in the presence of silyl alcohols, such as triethylsilanol. Poly(N‐isopropylacrylamide) with a racemo dyad content of 75% was obtained at ? 80 °C with a 4:1 triethylsilanol to monomer ratio loading. NMR analysis suggests that the mechanism for syndiotactic induction, in the presence of silyl alcohols, may be similar to that observed with alkyl alcohols. In this case, a 1:2 complex formation, via hydrogen bonding interactions, leads to the induction of syndiotactic specificity. Copyright © 2012 Society of Chemical Industry     

Polymerized ionic liquids with guanidinium cations as host for gel polymer electrolytes in lithium metal batteries

Polymerized ionic liquids (PILs) having guanidinium cations with different counter‐anions, such as PF₆^? and N(CF₃SO₂)₂^? (TFSI^?), were synthesized by copolymerization of a guanidinium ionic liquid monomer with methyl acrylate followed by an anion exchange reaction. Furthermore, incorporating a guanidinium ionic liquid, LiTFSI salt and nano‐size SiO₂, a quaternary gel polymer electrolyte based on one of the PILs as the polymer host was prepared. The quaternary gel polymer electrolyte was chemically stable even at a higher temperature of 80 °C in contact with the lithium anode. In particular, the electrolyte exhibited high lithium ion conductivity, wide electrochemical stability window and good lithium stripping/plating performance. Li/LiFePO₄ batteries with the quaternary gel polymer electrolyte at 80 °C had capacities of 140 and 130 mA h g^?1 respectively at 0.1 and 0.2 C current rates. Copyright © 2011 Society of Chemical Industry     

Possible Reaction Mechanism for the Formation of C60 From Naphthalene: A Semi-Empirical and Ab Initio Molecular Orbital Study

Abstract

Mechanism of C₆₀ formation from naphthalenes was studied by quantum chemical calculations. a patch up process of T-shape dimerization of naphthalenes followed by the intramolecular ring fusion, all through radical reactions, was proposed for a possible mechanism for the C₆₀ formation from naphthalenes. the reaction barrier was found to be less than 60-70 kcal/mol for each reaction step in this mechanism.     

Notch effect on the tensile properties of cold-rolled Ni3Al foils

Notch effect on the tensile properties of the Ni₃Al foils has been investigated as a function of notch geometry and foil’s thickness. Tensile tests along the rolling direction (RD) and the transverse direction (TD) showed that notch weakening occurred with introduce of a notch. Plastic deformation was observed locally at notch root and the effective stress concentration factor (k_e) was much lower than the theoretical stress concentration factor (K_t). Contrary to the anisotropy in fracture stress along the RD and the TD, k_e fell on the same curve. Crack initiation mechanism was different between two tensile directions, that is, cracks initiated along the shear band in the RD tension, while cracks initiated homogenously on the slip planes in the TD tension.