Biomedical subjects
Publications and source records attributed to Masaharu Ueno.
Asymmetric aldol reactions of ketene silyl acetals with aldehydes using an air-stable, storable chiral zirconium catalyst, which could be stored for at least 13 weeks at room temperature, proceeded smoothly to afford the desired adducts in high yields with high selectivity.
Phase-transfer alkylation in a microreactor proceeds smoothly, and the reaction has been found to be more efficient than that in a round-bottomed flask with vigorous stirring; we have observed by an optical microscope study that an interfacial area provided by organic and aqueous phases is more extended in a microreactor.
An air-stable, storable, and highly selective chiral Lewis acid catalyst for asymmetric Mannich-type reactions has been developed. The catalyst can be stored for more than three months in air at room temperature without loss of activity. Moreover, it has also been demonstrated that the catalyst can be recovered and reused. [structure: see text]
Optically active anti-alpha-methyl-beta-amino acid derivatives have been prepared based on catalytic enantioselective addition of propionate units to simple and inert imines using a chiral zirconium complex. High reactivity and selectivity with wide substrate scope were attained by using a new chiral ligand, (R)-6,6'-bis(pentafluoroethyl)-1,1'-bi-2-naphthol ((R)-6,6'-C(2)F(5)BINOL). The reactions using geometrically isomeric ketene silyl acetals gave excellent anti-selectivity with high enantiomeric excess in both cases. Synthetic utility of this reaction has been demonstrated by the preparation of various anti-alpha-methyl-beta-amino acid and trans-3,4-disubstituted beta-lactam derivatives.
The liposomal phase transition temperature was monitored in unstirred suspensions using a differential scanning calorimeter. The main and pre-transition temperatures under conditions of stirring were measured by the change in 90 degrees light scattering using a fluorescence spectrophotometer. Both methods show the same main transition temperature either with or without stirring. Temperature sensitive liposomes were made of DPPC (dipalmitoylphosphatidylcholine), DMPC (dimylisitoylphosphatidylcholine) or DSPC (distearoylphosphatidylcholine). The calcein release profile from the liposomes depends on the stirring time of the liposome suspension at the main transition temperature. For 1 h incubation, the leakage profile with and without stirring is similar. It had been hypothesized that temperature sensitive liposomes released drug at the main-transition temperature. However, calcein leakage from liposomes is observed also at the pre-transition temperature. Thus, a liposomal encapsulated drug will likely leak from DPPC liposomes at body temperature (37 degrees C), even if the liposomes were designed to have a higher main transition temperature.
The effects of sub-solubilizing concentrations of sodium cholate (Na-chol) on several physicochemical properties of phosphatidylcholine (PC) small unilamellar vesicles (SUV) were considered in connection with the initial stage of membrane solubilization. ESR spectra of 12-doxylstearic acid (12-DS) in phosphatidylcholine from egg yolk (EPC) or dimyristoylphosphatidylcholine (DMPC) SUV at low concentrations (insufficient to destroy the vesicles) of Na-chol were composed of two (a strongly immobilized and an additional weakly immobilized) immiscible components. The origin of the additional bands was phase separation which occurred in the hydrophobic parts of PC SUV in the presence of Na-chol. Differential scanning calorimetry measurements demonstrated that the mixed DMPC/Na-chol SUV possessed two (a sharp low-temperature and a broad high-temperature) endothermic peaks, which is consistent with the coexistence of two immiscible phases in the vesicular membranes. zeta Potentials of the EPC/Na-chol SUV revealed that high anionic densities appeared on the surfaces of the SUV at a Na-chol concentration slightly below the upper boundary of the vesicle region. Thus, the initial stage of the solubilization of PC SUV by Na-chol was caused by the aggregation of hydrophobic parts of PC membranes, followed by the occurrence of high anionic densities on the surfaces of the vesicles. The fact that removal of Na-chol from PC/Na-chol mixed systems preferentially resulted in the formation of small vesicles might originate from these anionic charges.
Egg phosphatidylcholine (EggPC) or dimyristoylphosphatidylcholine (DMPC) liposomes containing polyethylene glycol (PEG)-lipids covering a range of 0-30 mol% have been prepared by Extrusion method. The physicochemical properties including size evolution and calcein permeation were evaluated to investigate the effect of PEG-lipids on bilayer structure. The results from quasielasetic light scattering (QELS), freeze-fracture microscopy, and gel exclusion chromatography revealed that presence of low concentration of PEG-lipid results in decreasing of vesicle size and further increase in the PEG-lipid concentrations lead to a transition from the lamellar membranes to micelles. The permeability for calcein increased with increase in concentration of distearoylphosphatidylethanolamine (DSPE)-PEG. On the other hand, the permeability decreased with low amount of cholesterol-PEG (blow 20% cholesterol-PEG) and increased with high amount of it. The maximum concentration of PEG-lipid that may be incorporated without alteration of the liposome structure depends on the composition of the bilayer. The concentration of DSPE-PEG2000 incorporated into vesicles without damaging vesicle structures were <20 mol% for EggPC and <10% for DMPC.
Antimalarial alkaloids febrifugine (1) and isofebrifugine (2) were efficiently synthesized from simple achiral starting materials on the basis of the catalytic asymmetric synthesis. The first key reaction was performed using the tin(II)-mediated catalytic asymmetric aldol protocol to afford chiral aldehyde 3 in high yield with high diastereo- and enantioselectivities. The second key step, a Mannich-type reaction, did not give satisfactory results according to the conventional methods. We then developed a novel aqueous Mannich-type three-component reaction of an aldehyde, an amine, and a vinyl ether using a Lewis acid-surfactant combined catalyst (LASC), and the key intermediates 16 and 17 were obtained in high yields. The final coupling reactions of bromoacetone 14 with 4-hydroxyquinazoline were carried out using basic conditions, and successive deprotection gave 1 and 2, respectively, without any isomerization. These unambiguous total asymmetric syntheses revealed that the absolute configurations of febrifugine and isofebrifugine were not (2'S,3'R) and (2'R,3'R) as reported previously but (2'R,3'S) and (2'S,3'S), respectively (1' and 2'). Finally, antimalarial activities of the synthesized febrifugine and isofebrifugine, and their antipodes, were examined. It was revealed that the activities and selectivities of natural febrifugine and isofebrifugine were much higher than those of the antipodes.