Yoshiki Oda

Design, synthesis and evaluation of D-galactose-β-cyclodextrin conjugates as drug-carrying molecules

Several kinds of D-galactose-beta-cyclodextrin conjugates having a phenyl group in the spacers between the D-galactose and beta-cyclodextrin were designed and synthesized as drug-carrying molecules. Their evaluation as drug-carrying molecules was done by measuring the molecular interactions with the anticancer agent, doxorubicin, and with the d-galactose-binding peanut lectin using an SPR optical biosensor. The SPR analyses showed that these conjugates had remarkably high inclusion associations of 10(5) approximately 10(7)M(-1) levels for the immobilized doxorubicin. Their association constants for immobilized peanut lectin were at the level of 10(4) approximately 10(5)M(-1), as we expected. These conjugates will be useful drug-carrying models which can site-specifically carry doxorubicin to the cells containing D-galactose-binding lectin.

β-Cyclodextrin Conjugates with Glucose Moieties Designed as Drug Carriers: Their Syntheses, Evaluations Using Concanavalin A and Doxorubicin, and Structural Analyses by NMR Spectroscopy

Three kinds of beta-cyclodextrin derivatives conjugated with glucose moieties, which were expected as models for a drug carrier targeting the drug delivery systems, were designed and synthesized from beta-cyclodextrin and the natural product, 4-hydroxyphenyl-beta-D-glucopyranoside called arbutin. Arbutin was used because it had a phenyl group with a hydroxyl function which could be used to link the glucose moiety to beta-cyclodextrin. The evaluations of these conjugates as the drug-carrying molecules were done by investigating the molecular interactions with the carbohydrate-binding Concanavalin A (Con A) lectin and the anticancer agent, doxorubicin (DXR), using an SPR optical biosensor. The association constants of the conjugates with immobilized Con A were 2.0 x 10(3) approximately 8.8 x 10(3) M(-1). The result showed that the Con A bound to the glucose moieties from arbutin in the conjugates with prospective association constants. The inclusion associations of the conjugates with immobilized DXR reached 2.2 x 10(5) approximately 1.4 x 10(8) M(-1). The extremely high inclusion associations for DXR suggested their potential abilities as drug-carrying molecules for carrying DXR. The NMR analyses indicated that the phenyl group of the conjugates greatly served to increase the inclusion associations for DXR. In their DXR inclusion complexes, the formation of the stacking complexes by the pi;-pi interactions between the phenyl groups and the included DXR also enhanced their inclusion abilities for DXR.

Improvement of some physicochemical properties of arundic acid, (R)-(-)-2-propyloctanonic acid, by complexation with hydrophilic cyclodextrins.

Arundic acid, (R)-(-)-2-propyloctanonic acid, is a novel neurological agent for intractable neurodegenerative diseases. However, arundic acid, an oily drug, has low aqueous solubility and severe bitter/irritating tastes. Consequently, these physicochemical properties of arundic acid need to be improved to develop its pharmaceutical preparations. In the present study, we evaluated whether parent cyclodextrins (CyDs) and 2-hydroxypropylated CyDs (HP-CyDs) can interact with arundic acid, and have powderization, solubilization and taste-masking properties. Of various CyDs, HP-β-CyD had the most potent solubilizing effect for arundic acid. UV and (1)H NMR spectroscopic studies demonstrated that arundic acid formed inclusion complexes with CyDs at a molar ratio of 1:1 in solution. The complexation with CyDs changed an oily form of arundic acid to a solid form. The gustatory sensation studies indicate that of various CyDs, HP-β-CyD and γ-CyD showed the most significant taste-masking effects in solution and powders, respectively. HP-β-CyD significantly reduced the response of the electric potential caused by the adsorption of arundic acid to the taste sensor. These results suggest that hydrophilic CyDs have potential as multifunctional excipients for preparing solutions and powders containing arundic acid.

Synthesis of a Novel D-Glucose-Conjugated 15-Crown-5 Ether with a Spiro Ketal Structure

This paper describes a synthetic approach to a novel D-glucose-conjugated 15-crown-5 ether having a spiroketal structure starting from a 1-C-vinylated glucose derivative. The approach consists of the glycosylation of the vinylated glucose derivative to give an ethyleneoxy spacer derivative using bismuth(III) triflate, the conversion of the 1-C-vinyl group of the glucoside produced into a carboxylic acid group, and the intramolecular condensation between the carboxyl group and the terminal hydroxyl group in the ethyleneoxy spacer. A D-glucose-conjugated 15-crown-5 ether having a unique spiroketal structure was thus successfully synthesized.

Synthesis, structure, and evaluation of a β-cyclodextrin-artificial carbohydrate conjugate for use as a doxorubicin-carrying molecule.

This paper describes the synthesis of a β-cyclodextrin (β-CyD) derivative conjugated with a C,C-glucopyranoside containing a benzene unit. Its doxorubicin-inclusion ability and structure are also discussed. SPR analysis revealed that the β-CyD conjugate had a high inclusion association value of 3.8×10(6)M(-1) for immobilized doxorubicin. NMR structural analysis suggested that its high doxorubicin-inclusion ability was due to the formation of the inclusion complex as a result of the π-π stacking interaction between the benzene ring of the conjugate and the A ring of doxorubicin.

L-fructo- and D-psicofuranosylation reactions catalyzed by scandium triflate

This paper describes the formation of L-fructo- and D-psicofuranosidic bonds by the scandium triflate catalyzed glycosidation. The reaction of the benzoylated L-fructofuranosyl acetate with an alcohol in the presence of 5 mol% scandium triflate in toluene at room temperature for 3 h stereoselectively afforded the corresponding α-L-fructofuranoside in good yields. Several α-D-psicofuranosides were predominantly obtained in good yields by the reactions between the benzoylated D-psicofuranosyl acetate and alcohols under similar reaction conditions. This method successfully provided the sucrose mimics composed of D-glucopyranose and L-fructofuranose or D-psicofuranose.

Identification of the inclusion complexation between phenyl β-d-(13C6)glucopyranoside and α-cyclodextrin using 2D 1H or 13C DOSY spectrum

This study describes the 2D 1H and 13C diffusion-ordered NMR spectroscopy (DOSY) experiments using the mixed sample of α-cyclodextrin (α-CyD) and phenyl β-d-(13C6)glucopyranoside (1). Both the 2D 1H and 13C DOSY spectra showed the component with a diffusion coefficient different from those of α-CyD and 1, which suggested the inclusion complexation of α-CyD with 1.

6,7,8,10-Tetra-O-benzyl-1,2,3,4-tetradeoxy-α-D-gluco-dec-5-ulopyranosyl 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranoside

The title compound 1 was synthesized by the coupling reaction of 6,7,8,10-tetra-O-benzyl-1,2,3,4-tetradeoxy-α-D-gluco-dec-5-ulopyranose (2) with 2,3,4,6-tetra-O-benzyl-D-glucopyranose (3) in the presence of 5 mol% bismuth(III) triflate in dichloromethane at 0 °C.

A synthetic approach to anhydroketopyranoses having a 6,8-dioxabicyclo〔3.2.1〕octane structure from ketopyranoses

We investigated a synthetic approach to the anhydroketopyranoses having a 6,8-dioxabicyclo[3.2.1]octane structure from D -glucopyranose derivatives. The paper describes the nucleophilic addition of the organometallic reagents RLi or RMgX to the glucono-1,5-lactone derivatives to produce the ketopyranose derivatives having a glucose backbone and their intramolecular cyclization into the desired structural anhydroketopyranoses.

pH-Dependent exhibition of hemolytic activity by an extract of Hypsizygus marmoreus fruiting bodies

The current study found that an extract from the fruiting bodies of the edible mushroom Hypsizygus marmoreus exhibited hemolytic activity against sheep red blood cells when its pH was lowered. Although hemolytic activity was not detected when an extract had a neutral pH, an extract with a low pH exhibited potent hemolytic activity. The maximal hemolytic activity was exhibited by an extract with a pH of 5.5. A heat-treated extract did not exhibit hemolytic activity before its pH was lowered, and that activity was inhibited in the presence of PMSF and EDTA. The turbidity of the extract increased during lowering of its pH, and the precipitate fraction exhibited hemolytic activity. Fractionation by a modified Bligh and Dyer method and TLC analyses suggested that a hemolytic compound in the extract might be a type of lipid. These results suggest that a hemolytic lipid-like compound in an extract of H. marmoreus fruiting bodies may be released by a non-active precursor substance(s) through metalloenzyme(s) while the extract has a low pH.