Bitterness evaluation of medicines for pediatric use by a taste sensor

The purpose of this study was to evaluate the bitterness of 18 different antibiotic and antiviral drug formulations, widely used to treat infectious diseases in children and infants, in human gustatory sensation tests and using an artificial taste sensor. Seven of the formulations were found to have a bitterness intensity exceeding 1.0 in gustatory sensation tests (evaluated against quinine as a standard) and were therefore assumed to have an unpleasant taste to children. The bitterness intensity scores of the medicines were examined using suspensions in water or an acidic sports drink. In the case of three macrolide antibiotic formulations containing erythromycin (ERYTHROCIN dry syrup), clarithromycin (CLARITH dry syrup for pediatric), and azithromycin (ZITHROMAC fine granules for pediatric use), the bitterness intensities of suspensions in acidic sports drinks were dramatically enhanced compared with the corresponding scores of suspensions in water. This enhancement could be predicted using the taste sensor. On the other hand, a reduction of bitterness intensity was observed for an acidic sports drink suspension of an amantadine product (SYMMETREL fine granules) compared with an aqueous suspension. This reduction in bitterness could also be predicted using the taste sensor output value. Thus, the taste sensor could predict whether or not suspension in an acidic sports drink would enhance or reduce the bitterness intensity of pediatric drug formulations, compared with suspensions in water.     

Metal-complex assemblies constructed from the flexible hinge-like ligand H2bhnq: structural versatility and dynamic behavior in the solid state

Novel metal-complex assemblies constructed from the flexible hinge-like ligand H(2)bhnq (H(2)bhnq=2,2'-bi(3-hydroxy-1,4-naphthoquinone)) have been synthesized. The X-ray crystal structures of these compounds reveal that four types of architectures are accessible by variation of the metal ions. In copper(II) compounds 1-3, the chelating bhnq(2-) ions bridge copper(II) centers to form one-dimensional zigzag chains. The chains of 1-3 are arranged by hydrogen-bonding interactions and stacking interactions to produce porous structures. Cobalt(II) and zinc(II) compounds 4 and 5 form one-dimensional helical chains. In 4 and 5, the crystal packing induces spontaneous resolution of the helical chains with chiral cavities formed perpendicular to the helices. Nickel(II) compounds 6 and 7 form cyclic tetramers. The fourth architecture, a dimer (compound 8), is obtained by the reaction of zinc(II) and bhnq(2-) in MeOH. In these compounds, changes of the dihedral angles and the metal-coordination mode of the bhnq(2-) ion induce the structural versatility. The assemblies of the zigzag chains of the copper(II) compounds exhibit reversible vapochromic behavior. UV/Vis, powder X-ray diffraction, EPR, and adsorption isotherm measurements indicate that this vapochromic behavior is based on the hinge-like flexibility of the bhnq(2-) ion.     

Detection of the His-heme Fe2+-NO species in the reduction of NO to N2O by ba3-oxidase from thermus thermophilus

Reaction pathways in the enzymatic formation and cleavage of the N-N and N-O bonds, respectively, are difficult to verify without the structure of the intermediates, but we now have such information on the heme a(3)(2+)-NO species formed in the reaction of ba(3)-oxidase with NO from resonance Raman spectroscopy. We have identified the His-heme a(3)(2+)-NO/Cu(B)(1+) species by its characteristic Fe-NO and N-O stretching frequencies at 539 and 1620 cm(-)(1), respectively. The Fe-NO and N-O frequencies in ba(3)-oxidase are 21 and 7 cm(-)(1) lower and higher, respectively, than those observed in Mb-NO. From these results and earlier Raman and FTIR measurements, we demonstrate that the protein environment of the proximal His384 that is part of the Q-proton pathway controls the strength of the Fe-His384 bond upon ligand (CO vs NO) binding. We also show by time-resolved FTIR spectroscopy that Cu(B)(1+) has a much lower affinity for NO than for CO. We suggest that the reduction of NO to N(2)O by ba(3)-oxidase proceeds by the fast binding of the first NO molecule to heme a(3) with high-affinity, and the second NO molecule binds to Cu(B) with low-affinity, producing the temporal co-presence of two NO molecules in the heme-copper center. The low-affinity of Cu(B) for NO binding also explains the NO reductase activity of the ba(3)-oxidase as opposed to other heme-copper oxidases. With the identification of the His-heme a(3)(2+)-NO/Cu(B)(1+) species, the structure of the binuclear heme a(3)-Cu(B)(1+) center in the initial step of the NO reduction mechanism is known.     

Controllable donor-acceptor neutral [2]rotaxanes

In pursuit of a neutral bistable [2]rotaxane made up of two tetraarylmethane stoppers--both carrying one isopropyl and two tert-butyl groups located at the para positions on each of three of the four aryl rings--known to permit the slippage of the pi-electron-donating 1,5-dinaphtho[38]crown-10 (1/5DNP38C10) at the thermodynamic instigation of pi-electron-accepting recognition sites, in this case, pyromellitic diimide (PmI) and 1,4,5,8-naphthalenetetracarboxylate diimide (NpI) units separated from each other along the rod section of the rotaxane's dumbbell component, and from the para positions of the fourth aryl group of the two stoppers by pentamethylene chains, a modular approach was employed in the synthesis of the dumbbell-shaped compound NpPmD, as well as of its two degenerate counterparts, one (PmPmD) which contains two PmI units and the other (NpNpD) which contains two NpI units. The bistable [2]rotaxane NpPmR, as well as its two degenerate analogues PmPmR and NpNpR, were obtained from the corresponding dumbbell-shaped compounds NpPmD, PmPmD, and NpNpD and 1/5DNP38C10 by slippage. Dynamic 1H NMR spectroscopy in CD2Cl2 revealed that shuttling of the 1/5DNP38C10 ring occurs in NpNpR and PmPmR, with activation barriers of 277 K of 14.0 and 10.9 kcal mol(-1), respectively, reflecting a much more pronounced donor-acceptor stabilizing interaction involving the NpI units over the PmI ones. The photophysical and electrochemical properties of the three neutral [2]rotaxanes and their dumbbell-shaped precursors have also been investigated in CH2Cl2. Interactions between 1/5DNP38C10 and PmI and NpI units located within the rod section of the dumbbell components of the [2]rotaxane give rise to the appearance of charge-transfer bands, the energies of which correlate with the electron-accepting properties of the two diimide moieties. Comparison between the positions of the visible absorption bands in the three [2]rotaxanes shows that, in NpPmR, the major translational isomer is the one in which 1/5DNP38C10 encircles the NpI unit. Correlations of the reduction potentials for all the compounds studied confirm that, in this non-degenerate [2]rotaxane, one of the translational isomers predominates. Furthermore, after deactivation of the NpI unit by one-electron reduction, the 1/5DNP38C10 macrocycle moves to the PmI unit. Li+ ions have been found to strengthen the interaction between the electron-donating crown ether and the electron-accepting diimide units, particularly the PmI one. Titration experiments show that two Li+ ions are involved in the strengthening of the donor-acceptor interaction. Addition of Li+ ions to NpPmR induces the 1/5DNP38C10 macrocycle to move from the NpI to the PmI unit. The Li+-ion-promoted switching of NpPmR in a 4:1 mixture of CD2Cl2 and CD3COCD3 has also been shown by 1H NMR spectroscopy to involve the mechanical movement of the 1/5DNP38C10 macrocycle from the NpI to the PmI unit, a process that can be reversed by adding an excess of [12]crown-4 to sequester the Li+ ions.     

1,2-silyl-migrative cyclization of vinylsilanes bearing a hydroxy group: stereoselective synthesis of multisubstituted tetrahydropyrans and tetrahydrofurans(1)

Acid-catalyzed intramolecular addition of a hydroxy group to alpha-alkylated vinylsilanes has been studied. Treatment of (Z)-5-alkyl-5-silyl-4-penten-1-ols 1 (R = alkyl) with 5 mol % TiCl(4) in CHCl(3) gave trans-2-alkyl-3-silyltetrahydropyrans 2 exclusively (trans/cis = >99/1 to 97/3). The cyclization efficiency and rate strongly depended on the geometry of the C-C double bond and the silyl group. The use of (E)-vinylsilanes resulted in lower yields with poor cis-selectivity. In the cyclization of (Z)-1 (R = Bu), the silyl group used, the reaction time, and the yield of 2 were as follows: SiMe(2)Ph, 9.5 h, 75%; SiMe(3), 7.5 h, 66%; SiMePh(2), 24 h, 58%; SiMe(2)-t-Bu, 0.75 h, 85%; SiMe(2)Bn, 1.5 h, 78%. This 1,2-silyl-migrative cyclization could be applied to stereoselective synthesis of trisubstituted tetrahydropyrans. The acid-catalyzed reaction of 1-, 2-, or 3-substituted (Z)-5-silyl-4-nonen-1-ols 8 gave r-2,t-3,c-6-, r-2,t-3,t-5-, or r-2,t-3,c-4-trisubstituted tetrahydropyrans with high diastereoselectivity, respectively. (Z)-4-Alkyl-4-silyl-3-buten-1-ols 5 as well as 1 underwent the 1,2-silyl-migrative cyclization to give 2-alkyl-3-silyltetrahydrofurans 6 with high trans-selectivity. This silicon-directed cyclization was also available for the stereoselective synthesis of tri- and tetrasubstituted tetrahydrofurans.     

Surface-potential reversibility of an amino-terminated self-assembled monolayer based on nanoprobe chemistry

Nanoprobe chemistry offers a promising approach for the construction of nanostructures consisting of organic molecules by employing the tip of a scanning probe microscope. In a previous report, we demonstrated that a nitroso-terminated surface on an organosilane self-assembled monolayer could be converted into an amino-terminated surface by applying such a nanoprobe electrochemical technique. This paper reports on surface-potential reversibility originating from a reversible chemical reaction between amino and nitroso groups. In addition, we demonstrate surface-potential memory based on this chemical reversibility. Amino-terminated SAMs were prepared from p-aminophenyl-trimethoxysilane through chemical vapor deposition. Surface potentials were acquired by Kelvin force microscopy. When scanning probe lithography was conducted with a gold tip at positive-bias voltages, the surface potential of the scanned area shifted dramatically in the negative direction. Scanning with negative-bias voltages led to positive shift in the surface potential of the scanned area. The surface potential could be recovered even after multiple scannings with positive and negative applied bias voltages. On the basis of this discovery, we also succeeded in demonstrating surface-potential memory via our nanoprobe electrochemical technique.     

"Chiral perturbation factor" approach reveals importance of entropy term in stereocontrol of the 2,4-pentanediol-tethered reaction

The stereocontrol mechanism of the 2,4-pentanediol (PD)-tethered reaction was studied in detail using a reaction system consisting of phenyl and rhodium carbenoid moieties. Different tethers were examined to analyze the effects of the methyl groups on the PD tether. Among the reactions with these tethers, the PD tether achieves an unmeasurably high stereoselectivity in a diastereomeric ratio of >500. Another tether showing a high but measurable stereoselectivity in a ratio of 41 is mostly controlled by the entropy term. To clarify the role of the methyl groups on the chiral tethers, which are the origin of the stereocontrol, the "chiral perturbation factor" is introduced. This parameter is defined as the rate of a chiral reaction relative to that of an achiral reference reaction. By analyzing the temperature dependence of the chiral perturbation factors for different chiral-tethered reactions, high potentials of the PD-tethered reaction in its stereocontrol are concluded to be due to the entropy term.     

Syntheses and Characterization of Polymetallosiloxanes from Silicic Acid and Metal Chlorides

Syntheses and characterization of polymetallosiloxanes by the non-hydrolysis sol-gel process using no metal alkoxides were investigated. The reaction of silicic acid (SA) with MCl₄ (M = Ti, Zr) in the molar ratios SA/MCl₄ = 0.5–3.0 using a tetrahydrofuran-methanol solvent formed polymetallosiloxane (PMS), which was insoluble in organic solvents regardless of the molar ratio. The PMS was isolated as esterified polymetallosiloxane by esterification with isopropyl alcohol for various periods, which were soluble in methanol, acetone, and tetrahydrofuran. The number average molecular weight was 1000–3200 for esterified polytitanosiloxane and 3400–11000 for esterified polyzirconosiloxane. Esterified polymetallosiloxanes had no melting point but decomposition point. The results of analytical data indicated that esterified polymetallosiloxane and/or polymetallosiloxane consisted of the main chain of Si–O–Si and Si–O–M linkage with the pendants of alkoxy, silanol, and chloro group.     

AISM Data 43-3-01 Seismograms of foreshocks of 1982 Urakawa-oki earthquake

AISM Data Library

AISM Data 43-3-01 Seismograms of foreshocks of 1982 Urakawa-oki earthquake