Naoki Matsunaga

Synthesis of Ether- and Imino-Linked OctylN-Acetyl-5a′-carba-β-lactosaminides and -isolactosaminides: Acceptor Substrates for α-(1→3/4)-Fucosyltransferase, and Enzymatic Synthesis of 5a′-Carbatrisaccharides

Synthesis of ether-linked octyl 5a′-carba-β-lactosaminide 3 and -isolactosaminide 5 was carried out in seven steps, starting from the coupling products of 1,2-anhydro-5a-carba-β-D-mannopyranose derivative 7, and the oxide anions generated from the octyl N-acetyl-β-D-glucosaminide derivatives 13 and 16, respectively, under basic conditions. The 5a-carba-α-D-mannopyranose residues of the coupling products 17 and 26 were transformed into the β-D-gluco configuration through epimerization of the respective 2′-oxo derivatives 19 and 28, and selective reduction, and then into the β-D-galacto configuration by direct nucleophilic substitution of their 4′,6′-dimesylates 23 and 31 with an acetate ion. Biological assay has shown that 3 is an acceptor substrate for human-milk α-(13/4)-fucosyltransferase and, interestingly, 5 is not. In addition, the imino-linked congeners 4 and 6 have been synthesized by coupling of the 4-amino-4-deoxy- and 3-amino-3-deoxy derivatives 37 and 41 of octyl N-acetyl-β-D-glucosaminide, and the carba-sugar epoxide 8, respectively, and subsequent deprotection. Compound 4 is a substrate while 6 is neither a substrate nor an inhibitor for fucosyltransferase. Small-scale enzymatic synthesis was carried out by treatment of 3 and 4 with GDP-fucose and milk fucosyltransferase, which resulted in conversion into the corresponding trisaccharides 47 and 48, respectively.

Temperature dependence of NO to NO2 conversion by n-butane and n-pentane oxidation

An experimental and detailed chemical kinetic modeling investigation of the temperature-dependentrole of n-butane and n-pentane oxidation on the NO to NO2 conversion is presented. An atmospheric pressure, quartz flow reactor was used to examine the NO oxidation to NO2 behavior for the 600 to 1100 K temperature range and residence times from 0.16 to 1.46 s. In the experiment, probe measurement of the species concentrations was performed in the flow reactor using a mixture of NO (20 ppm)/air/hydrocarbon (10 ppm). In the chemical kinetic calculation, the time evolution of NO, NO2, hydrocarbons, and reaction intermediates were evaluated using a n-butane oxidation model coupled with a nitrogen oxides submechanism for all temperatures. The detailed chemical kinetic model consisted of 897 reactions and 158 species. The experimental results show n-pentane promoting the NO to NO2 conversion to a greater extent thann-butane for the entire temperature range. This may be explained by n-pentane oxidation exhibiting a vigorous chain-branched hydroperoxy-pentylperoxy radical isomerization kinetic system more so than found in n-butane. Kinetic calculations performed on the n-butane oxidation system revealed that the NO to NO2 conversion is strongly temperature dependent. The NO+HO2=NO2+OH and alkylperoxy +NO=alkyloxy+NO2 reactions play an important role in converting NO to NO2 at the lower temperatures in this study. However, as the temperature increases toward 800–900 K, the butyl+O2 and hydroperoxy-butyl+O2 network of reactions undergoes reaction reversal and allows other reaction channels to be accessed which heavily promotes NO to NO2 conversion. Above 900 K, the decrease in NO2 concentration is attributed to NO2+HO2=HONO+O2, HONO(+M)=NO+OH(+M), and NO2+O=NO+O2 destruction reactions. Consequently, the change of HO2 formation with temperature plays the most important role for the temperature dependence of the NO to NO2 conversion.

Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia

Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.

Reactive Absorption of NO2 by Water in the NOx Measurement System

In this study, firstly it was demonstrated that the absorption of NO2 by condensed water in the sampling system might lead to considerable errors in the measurement of NOx for combustion gases containing relatively high concentration of NO2. Secondly, the loss of NO2 into water was systematically measured using bubblers in series or an NO2 absorption tube (a horizontal tube partly full of water). NO2/air mixtures were passed through the bubblers or the NO2 absorption tube and then analyzed by a chemiluminescent NOx analyzer. The initial NO2 concentration and water temperature were varied in the ranges 20-300 ppm and 0-30°C, respectively. The ratio of the decrease in the concentration of NO2 to the initial value Δ [NO2] / [NO2] 0 is found to be proportional to the surface area of water and inversely proportional to the volume flow rate of the mixture but practically independent of the residence time in the NO2 absorption tube. Also, Δ [NO2] / [NO2] 0, gradually increases with increasing the initial concentration of NO2 but it is independent of those of NO and O2. The temperature dependence of Δ [NO2] / [NO2] 0 is found to be negative and of an Arrhenius relationship. The species balance between the gaseous and liquid phases was also verified. Finally, based on a simple model and the present experimental data, an equation for estimating the magnitude of the loss of NO2 was developed.