Tatsuya Shirahata

Pinellic acid from the tuber of Pinellia ternata Breitenbach as an effective oral adjuvant for nasal influenza vaccine

This study describes the isolation, purification, characterization, and adjuvant activity of an orally active adjuvant substance from the tuber of Pinellia ternata, as an active herbal component of the traditional Japanese herbal (Kampo) medicine, Sho-seiryu-to (SST, Chinese name: Xiao-Qing-Long-Tang), which has been reported to show oral adjuvant activity for nasally administered influenza HA vaccine [Int. J. Immunopharmacol. 16 (1994) 605]. The active compound was identified as 9S, 12S, 13S-trihydroxy-10E-octadecenoic acid using infrared spectra, proton magnetic resonance, mass spectrometry, and circular dichroism, and named pinellic acid. Oral administration of pinellic acid (1 microg) to BALB/c mice given primary and secondary intranasal inoculations of influenza HA vaccine (1 microg) enhanced antiviral IgA antibody (Ab) titers 5.2- and 2.5-fold in nasal and bronchoalveolar washes, respectively, and antiviral IgG Ab titers 3-fold in bronchoalveolar wash and serum. Intranasal administration of pinellic acid (1 microg) with influenza HA vaccine (1 microg) slightly enhanced antiviral IgG Ab titers in bronchoalveolar wash and serum but not antiviral IgA Ab titers in nasal and bronchoalveolar washes. Pinellic acid showed no hemolytic activity. The results of this study suggest that pinellic acid may provide a safe and potent oral adjuvant for nasal influenza HA vaccine.

Total synthesis of pinellic acid, a potent oral adjuvant for nasal influenza vaccine. Determination of the relative and absolute configuration

Abstract Pinellic acid ( 1 ), isolated from a medicinal plant Pinelliae tuber, has potent adjuvant activity. The absolute configuration of pinellic acid was expected by derivatization of this compound and CD exciton chirality method. A convergent synthetic route to pinellic acid has been developed via regioselective asymmetric dihydroxylation and stereoselective reduction. The absolute configuration of pinellic acid was determined to be 9S,12S,13S, by comparing with the spectra data of natural and synthetic compounds.

Asymmetric Total Synthesis of Neoxaline

A first asymmetric total synthesis and determination of the absolute configuration of neoxaline has been accomplished through the highly stereoselective introduction of a reverse prenyl group to create a quaternary carbon stereocenter using (-)-3a-hydroxyfuroindoline as a building block, construction of the indoline spiroaminal via cautious stepwise oxidations with cyclizations from the indoline, assembly of (Z)-dehydrohistidine, and photoisomerization of unnatural (Z)-neoxaline to the natural (E)-neoxaline as the key steps.

Total synthesis and adjuvant activity of all stereoisomers of pinellic acid

Pinellic acid is a novel and potentially useful oral adjuvant when used in conjunction with intranasal inoculation of influenza HA vaccines. All stereoisomers of pinellic acid have been synthesized via regioselective asymmetric dihydroxylation, regioselective inversion, and stereoselective reduction, and their adjuvant activities were characterized. Among this series of isomers, 9S, 12S, 13S compound has the most potent adjuvant activity. Structure-activity relationships are discussed.

Oral adjuvant activity for nasal influenza vaccines caused by combination of two trihydroxy fatty acid stereoisomers from the tuber of Pinellia ternata

Pinellic acid from the tuber of Pinellia ternata was isolated as an effective oral adjuvant for nasal influenza vaccine, and identified 9S,12S,13S-trihydroxy-10E-octadecenoic acid (9S,12S,13S) by the enantioselective total synthesis [Nagai et al., Int. Immunopharmacol., 2, 1183-93 (2002); Shirahata et al., Tetrahedron, 62, 9483-96 (2006)]. However, present study showed that synthetic 9S,12S,13S that was nearly 100% pure was not effective as an oral adjuvant. HPLC analysis also showed that the adjuvant active pinellic acid fraction from tuber of P. ternata contained the 9S,12S,13S as the main component and at least two minor components. Therefore seven other chemically synthesized stereoisomers were tested in combination with the 9S,12S,13S for oral adjuvant activity. Only the 9S,12S,13S in combination with the 9S,12R,13R isomer in a weight% ratio of 90.4:9.6 (pinellic acid mixture, PAM) was a potent oral adjuvant and elicited both antiviral IgA antibody (Ab) in bronchoalveolar lavage fluids and nasal washes and antiviral IgG(1) Ab in mice sera. Oral administration of the PAM followed by nasal influenza vaccination and infection with A/PR/8/34 virus showed increases in survival rate (22%, control versus 78% test) in mice orally administered PAM as adjuvant. Histopathological examination of lung tissue of mice given oral PAM with vaccine followed by influenza virus infection showed attenuated infiltration of inflammatory cells with decreases in the alveolar spaces and increases in the alveolar septa. The result of this study refutes the our previous study and suggests that the combination of 9S,12S,13S and 9S,12R,13R isomers is necessary for effective oral adjuvant activity when used in conjunction with nasal influenza vaccine.

Iminimycin A, the new iminium metabolite produced by Streptomyces griseus OS-3601.

A new natural product, designated iminimycin A, was isolated from the cultured broth of a streptomycin-producing microbial strain, Streptomyces griseus OS-3601, via a physicochemical screening method using HP-20, silica gel and ODS column chromatographies and subsequent preparative HPLC. Iminimycin A is an indolizidine alkaloid, containing of an unusual iminium group and a cyclopropane ring with a triene side chain. The absolute configuration of iminimycin A was elucidated by NMR studies and electronic circular dichroism analysis. Iminimycin A shows anti-bacterial activity against Bacillus subtilis, Kocuria rhizophila and Xanthomonas campestris pv. orizae, and cytotoxic activity against HeLa S3 and Jurkat cells with IC50 values of 43 and 36 μM, respectively.

Asymmetric Total Synthesis of Indole Alkaloids Containing an Indoline Spiroaminal Framework

The total synthesis of the indole alkaloids, neoxaline, oxaline and meleagrin A, all containing a unique indoline spiroaminal framework, was accomplished through the stereoselective introduction of a reverse prenyl group to the congested benzylic carbon of furoindoline, a two-pot transformation of indoline (containing three nitrogen atoms at appropriate positions) to the featured indoline spiroaminal framework, and elimination of carbonate assisted by the adjacent imidazole moiety to construct the (E)-dehydrohistidine. The absolute stereochemistry of neoxaline was elucidated through our total synthesis. In addition, we evaluated the bioactivity, especially the anti-infectious properties, of neoxaline and oxaline, and of some synthetic intermediates.

Improved catalytic and stereoselective glycosylation with glycosyl N-trichloroacetylcarbamate: application to various 1-hydroxy sugars

Efficient catalytic and stereoselective glycosylation was achieved by activating a glycosyl N-trichloroacetylcarbamate with a catalytic amount of Lewis acid in the presence of a glycosyl acceptor and 5A molecular sieves. Catalytic one-pot dehydrative glycosylation of a 1-hydroxy carbohydrate was achieved stereoselectively by reaction with trichloroacetyl isocyanate, followed by activation with a catalytic amount of activators.

A new method for efficient coupling of indole and epoxide catalyzed with Yb(OTf)3, and application to the total synthesis of kurasoin B

The Yb(OTf) 3 catalyzed reaction between indole and epoxide in simple and mild condition was developed. This method is suitable for gram-scale synthesis of 3-indolelactic acid derivatives. The asymmetric synthesis of kurasoin B was achieved using chiral 3-indolelactic acid methyl ester as the starting material.

Syntheses and mucosal adjuvant activity of simplified oleanolic acid saponins possessing cinnamoyl ester.

A series of new simplified oleanolic acid saponins with a glycosyl ester moiety at C28, were efficiently prepared. Furthermore, the effect of nasal administration of the synthetic oleanolic acid saponins on the nasal anti-influenza virus antibody titer against secondary nasal inoculation of the influenza split vaccine was examined. The result revealed cinnamoyl saponin as a suitable candidate vaccine adjuvant.