Syntheses and reactions of some 2,3-disubstituted pyrazine monoxides

The reactions of 2,3-dimethyl- ( 4 ), 2,3-diphenyl- ( 6 ), and 2-methyl-3-phenyl-pyrazine monoxides ( 8 and 9 ) with phosphoryl chloride and acetic anhydride resulted in giving monochloro- and monacetoxy-pyrazines in almost all cases. However, the reaction of 6 with acetic anhydride afforded exceptionally a diacetoxydihydro-pyrazine. These products were converted further to hydroxy or dichloro derivatives.     

HPLC analysis of manno-oligosaccharides derived from Saccharomyces cerevisiae mannan using an amino column or a graphitized carbon column

The chromatographic behavior of manno-oligosaccharides derived from Saccharomyces cerevisiae mannan on two kinds of HPLC columns, an aminopropyl-silica column or a graphitized carbon column (GCC), was investigated. The order of elution of manno-oligosaccharides on both columns with acetonitrile-water was almost the same, that is, the retention increased with increasing molecular size. However, the GCC made it possible to isolate completely two isomers of mannotrioses (M(3)-1 and M(3)-2) with different linkage positions. We reinvestigated the structures of mannobiose (M(2)), M(3)s, and mannotetraose (M(4)) that were completely isolated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and NMR spectroscopy.     

Four new prostanoids: Claviridenone-A, -B, -C,and -D from the okinawan soft coral Clavularia viridis

The structures of four new prostanoids named claviridenone-a, -b, -c, and -d, which were isolated from the Okinawan soft coral Clavularia viridis, were elucidated as $\text{1}$, $\text{2}$, $\text{3}$, and $\text{4}$, respectively.     

Palladium charcoal-catalyzed Suzuki-Miyaura coupling to obtain arylpyridines and arylquinolines

A phosphine ligand, such as PPh3 or 2-(dicyclohexylphosphino)biphenyl, is essential for the Pd/C-catalyzed Suzuki-Miyaura coupling of halopyridines and haloquinolines, although it has been reported that the reaction of phenyl chlorides can be catalyzed by nonprereduced Pd/C without any additives. In the reactions of bromopyridines, bromoquinolines, 2-chloropyridines, and 2-chloroquinolines, PPh3 was effective enough to provide coupling products in good yields. However, in the reactions of 3-chloropyridine, 4-chloropyridine, and 6-chloroquinoline, sterically hindered 2-(dicyclohexylphosphino)biphenyl was indispensable as a ligand.     

Discovery of a novel and potent human and rat beta3-adrenergic receptor agonist, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid

In search for potent and selective beta3-adrenergic receptor (beta3-AR) agonists as potential drugs for the treatment of type II diabetes and obesity, a novel series of 1-(3-chlorophenyl)-2-aminoethanol derivatives were prepared and evaluated for their biological activity at human beta1-, beta2-, and beta3-ARs and rat beta3-AR expressed in Chinese hamster ovary (CHO) cells. Replacement of the right-hand side (RHS, benzene ring) in the 'first generation' beta3-AR agonists BRL 37344 and CL 316243 with a 1H-indole ring gave compound 31 with unique pharmacological properties among beta3-AR agonists. Initial in vitro assays showed that 31 possesses modest rat and human beta3-ARs agonistic activity. Introduction of various substituent into the indole nucleus of 31 afforded a number of compounds with good beta3-ARs agonistic activity. In particular, 90 having a carboxylic acid functionality at the 7-position of the indole nucleus showed the most potent human beta3-AR agonistic activity. Finally, optical resolution of 90 led to the identification of the most promising compound, [3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1H-indol-7-yloxy]acetic acid (96, AJ-9677). This compound exhibited potent human beta3-AR agonistic activity (EC50=0.062 nM, IA=116%) with 210- and 103-fold selectivity over human beta2-AR and beta1-AR, respectively. Compound 96 also exhibited potent rat beta3-AR agonistic activity (EC50=0.016 nM, IA=110%). Moreover, repeated oral administration of 96 inhibited body weight gain and significantly decreased glucose, insulin, free fatty acid, and triglyceride concentrations in plasma in KK-Ay/Ta mice. On the basis of this pharmacological profile, 96 entered clinical development as a drug for the treatment of type II diabetes and obesity.     

Alkali effects on the electronic states of K3C60 and Rb3C60

The electronic states in metallic alkali fullerides K₃C₆₀ and Rb₃C₆₀, are studied in detail by cw- and pulsed-ESR. The ESR linewidth associated with conduction electrons varies substantially, depending sensitively on the alkali metals used. It is clearly revealed that the linewidth is homogeneous and is strongly controlled by the spin-lattice relaxation times (T₁) determined via the spin-orbit interactions of the small fraction of s electrons remaining on the alkali atoms. The results indicate that the electron transfer from the alkali atoms to C₆₀ is not perfectly complete, with the remaining fraction being much greater in the tetrahedral sites than in the octahedral sites of the face-centered cubic lattice.     

Effect of cholesterol or phospholipids incorporation on vesicle formation of muramyldipeptide derivative B30-MDP

Summary The muramyldipeptide derivative B30-MDP has immunoadjuvant activity and vesicleforming ability in aqueous solutions. To assist in the clinical application of B30-MDP to liposomal vaccine, we investigated the physicochemical properties including membrane fluidity, surface charge and particle size of B30-MDP vesicles containing cholesterol, dipalmitoylphosphatidyl-choline (DPPC) or dipalmitoylphosphatidylglycerol (DPPG).The membrane fluidity of B30-MDP/cholesterol vesicles was slightly influenced by cholesterol concentration and temperature. The membrane fluidity of B30-MDP/phospholipid vesicle was dependent on temperature. ESR spectra clearly showed the good miscibility of cholesterol with B30-MDP and the occurrence of phase separation between B30-MDP and phospholipid.The surface charge and particle size of B30-MDP/cholesterol vesicles were hardly influenced by cholesterol concentration in the membrane because the membrane surface was covered with the hydrophilic region of B30-MDP. The effect of this hydrophilic region of B30-MDP on the surface charge and particle size of B30-MDP/phospholipid vesicle was greater than that of phospholipid.This study showed that the membrane structure of B30-MDP/cholesterol vesicle differed from that of B30-MDP/phospholipid vesicle. Further, the hydrophilic region of B30-MDP is considered to play an important role in the physicochemical properties and formation of the vesicle.     

Preparation of agglomeration-free hematite particles coated with silica and their reduction behavior in hydrogen

To prepare silica-coated hematite particles without agglomeration, the effects of solid fraction, ion content in solution, and designed layer thickness on agglomeration and dispersion behavior after silica coating were examined. Since the ion concentration remained high in suspension after the hematite particles were prepared, these particles formed aggregates by the compression of an electric double layer on the hematite and silica layer produced a solid bridge between primary hematite particles. Silica bridge formation and agglomeration were almost completely prevented by decreasing the ion concentration and solid fraction of the hematite particles. Furthermore, the effects of the silica-layer thickness and structure on the reduction of hematite to iron under hydrogen gas flow and the iron core stability under air were discussed. When the solid fraction was low in suspension to prevent agglomeration during coating, a densely packed structure of nanoparticles formed by heterogeneous nucleation was observed on the silica-layer surface. Since this structure could not completely prevent oxide diffusion, the layer thickness was increased to 40 nm to obtain a stable iron core under air. Although a dense uniform layer was produced at a high solid fraction during coating, its thickness was reduced to 20 nm to completely reduce hematite to iron.