Nobuto Minowa

Asymmetric synthesis of (+)-phosphinothricin and (+)-2-amino-4-phosphonobutyric acid

Abstract Asymmetric synthesis of (+)-phosphinothricin, (+)-2-amino-4-phosphono-butyric acid, and their enantiomers has been achieved by the Michael addition of chiral glycine Schiff bases to vinyl phosphorus compounds.

Protective effects of soyasapogenol A on liver injury mediated by immune response in a concanavalin A-induced hepatitis model

The present study was carried out to analyze the effects of soyasapogenol A on the liver injury mediated by the immune response in concanavalin A-induced hepatitis in mice. Soyasapogenol A reduced the number of infiltrating inflammatory cells in the liver and significantly lowered the elevated level of plasma tumor necrosis factor-alpha (TNF-alpha) 2 h after concanavalin A treatment, and then markedly reduced the elevated plasma alanine aminotransferase activity and decreased the number of apoptotic bodies in the liver parenchymal cells but not in the sinusoidal cells at 24 h. Since the effect of soyasapogenol A on the elevated plasma TNF-alpha level was not appreciable compared to the preventive effect of soyasapogenol A on the elevated plasma alanine aminotransferase level, these results suggest that soyasapogenol A directly prevents apoptosis of hepatocytes, and secondly, inhibits the elevation of plasma TNF-alpha, which consequently resulted in the prevention of liver damage in the concanavalin A-induced hepatitis model.

A practical synthesis of (+-)-phosphinothricine

Abstract A practical synthesis of (±)-phosphinothricide from trimethyl phosphite is described.

Effects of triterpene compounds on cytotoxicity, apoptosis, and immune response in cultured cells

To identify a candidate compound for therapy of chronic viral hepatitis, we screened a series of oleanene-type triterpenoids for their ability to alleviate aflatoxin B1 (AFB)-induced cytotoxicity, protect against actinomycin-tumor necrosis factor-induced apoptosis, and modulate the mixed lymphocyte reaction (MLR) in cultured cells. Glycyrrhizin at 200xa0μg/ml showed the strongest inhibitory effects on cytotoxicity without an immunomodulatory effect on MLR. In comparison, glycyrrhetic acid, the aglycone of glycyrrhizin, prevented apoptosis dose dependently and markedly decreased MLR with concomitant increases in concentration, but this compound failed to inhibit cytotoxicity. Among the compounds tested, soyasapogenol B at 100xa0μg/ml best alleviated cytotoxicity; it also protected against apoptosis at 50xa0μg/ml, and beginning at 1.0xa0μg/ml, this compound significantly increased MLR. At 25xa0μg/ml, soyasapogenol A, a group A saponin of soybean, showed maximum inhibition of cytotoxicity, but this inhibition rate tended to decrease with increasing dose rate. Uvaol markedly increased MLR with concomitant increases in concentration, and inhibited AFB-induced cytotoxicity, although it showed no protective effect on apoptosis. These screening data suggest that soyasapogenol B is a candidate therapeutic agent for chronic hepatitis because this compound can concomitantly (1) ameliorate cytotoxicity, (2) act as an antiapoptotic agent, and (3) increase MLR.

Derivatization of soyasapogenol A and their hepatoprotective activities

Fifteen derivatives of soyasapogenol A (1), which is another aglycon moiety of soyasaponins from soybean together with soyasapogenol B (2), were prepared and their in vitro hepatoprotective effects were evaluated.

Stereoselective synthesis of solanesol and all-trans-decaprenol

Allylic p-tolyl sulphones (5), (14), and (16) couple with allylic bromide (7) and geranyl bromide to produce regio- and stereo-chemically pure 1,5-diene systems. The coupling of all-trans-ω-bromogeranyl acetate (7) with geranyl p-tolyl sulphone (5) and higher isoprenologues (21), (24), and (27), followed by reductive elimination of p-tolysulphonyl group, furnishes a stereoselective synthesis of all-trans-polyprenols (3), (23),(26), and decaprenol (1b). Solanesol (1a) was synthesised using trans-4-chloroprenyl acetate (29) instead of (7).

Efficient synthesis of C(22) homologous derivatives of hepatoprotective soyasapogenol B

Stereochemical behavior in the addition reactions at C(22) of ketone 5 and exomethylene 6 was studied and C(22) homologous derivatives of soyasapogenol B were efficiently synthesized.

Design and synthesis of novel ring-expanded arbekacin analogues

Novel homologated aminoglycosides having a seven-membered ring were designed and synthesized by treatment of 5-keto arbekacin with diazomethane in CH 2 Cl 2 -Et 2 O. The ring-expanded arbekacin analogue showed good antibacterial activity against Staphylococcus aureus and Escherichia coli including aminoglycoside-resistant bacterial strain.

In vitro and in vivo antimicrobial activity of TS2037, a novel aminoglycoside antibiotic

To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel aminoglycoside antibiotic, and evaluated its biological properties. TS2037 showed broad-range, as well as robust antibacterial activities against Gram-positive and Gram-negative bacteria. The MIC50 and MIC90 of TS2037 against clinical isolates of MRSA (nu2009=u200954) were both 0.25u2009µg/mL, and no resistant strain was observed. The MIC50 and MIC90 of TS2037 against clinical isolates of P. aeruginosa (nu2009=u200954) were 1 and 4u2009µg/mL, respectively. TS2037 and arbekacin, anti-MRSA aminoglycoside, were more stable against AAC(6′)-APH(2″), aminoglycoside-6′-N-acetyltransferase and 2″-O-phosphotransferase, produced by resistant S. aureus than gentamicin. Therapeutic efficacies of TS2037 in the mouse models of systemic infection with MRSA were superior to those of arbekacin, vancomycin, and linezolid. The efficacy of TS2037 against systemic infection caused by P. aeruginosa producing AAC(6′)-II was superior to those of arbekacin and amikacin. In the nephrotoxicity risk screening, the release of free N-acetyl-β-d-glucosaminidase from the kidney epithelial cell line after treatment with TS2037 at 2.5 and 5.0u2009μM were 2.0 and 2.1 (U/L), respectively, which were about two times higher than those of arbekacin. In conclusion, TS2037 exhibited the most potent antibacterial activity among aminoglycosides tested against both MRSA and P. aeruginosa in vitro and in vivo, although its nephrotoxicity risk remains to be improved.