Takashi Kitayama

Unprecedented sugar-dependent in vivo antitumor activity of carbohydrate-pendant cis-diamminedichloroplatinum(II) complexes.

Eight carbohydrate-pendant platinum(II) complexes have been synthesized from carbohydrate-diamine conjugates. D-Glucose, D-mannose, D-galactose, D-xylose, and L-glucose are attached to the dichloroplatinum(II) moiety by 1,3- or 1,2-diaminopropane chelates through with an O-glycoside bond. All the carbohydrate moieties reduced the toxicity inherent with platinum(II) complexes.

The chemistry of zerumbone. Part 5: Structural transformation of the dimethylamine derivatives

Abstract Zerumbone ( 1 ) and its 6,7-epoxide ( 2 ) react with ammonia and dimethylamine regio- and stereospecifically, affording monoamines 3 , 4 , 7 and 8 . All adducts have the same relative configuration at C2 and C3. The conjugate amination is thermodynamically controlled to arrive at a single diastereomer. At 15°C 7 reacts with cyanide to give aminonitrile 10 as the single product, while at 30°C, acyclic aminonitrile 11 is also formed. The reaction with 8 affords at 0°C bicyclic aminonitrile 12 of the asteriscane skeleton, while at 30°C or higher temperature, mixtures of 12 and tricyclic nitriles 13 and 13′ are obtained. Refluxing of 7 , 8 and 10 in aqueous acetonitrile promotes scission of the zerumbone ring by retro-Mannich reaction to provide acyclic aldehydes 16–18 , respectively. The dimethylamino group of 7 , 8 and 10 is eliminated stereospecifically by Cope- and base-catalyzed eliminations to regenerate the zerumbone skeleton in the products 1 , 2 and 21 . Cope elimination of 12 results in a mixture of 13 and 13′ by deaminative transannular etherification.

Microbial asymmetric syntheses of 3-alkylphthalide derivatives

Abstract Phthalide derivatives, almost all of which have an S -configuration, have a wide range of activity and exist in Angerica sinensis Diels and Sligusticum wallichiii Franch. For the first time, optically active ( S )-3-methylphthalide derivatives were synthesized using two methods, asymmetric microbial reduction and microbial hydroxylation. For the first method, methyl 2-acetylbenzoate was synthesized as a substrate, which was reduced asymmetrically by Geotrichum candidum IFO 34614 to obtain ( S )-3-methylphtalide in 92% yield (99% enantiomeric excess, ee). For the second method, 2-ethylbenzoic acid was employed as a substrate which was hydroxylated asymmetrically at the benzylic position by either Pseudomonas putida ATCC 12633 or Aspergillus niger IFO 6661, whose fermentation was induced by o -toluic acid, to obtain ( S )-3-methylphthalide in 80% yield (99% ee). ( S )-3-Butylphthalide and ( S )-3-octylphthalide were obtained in the same manner in 12% yield (ee=99%) and 10% yield (ee=99%), respectively.

Attractive Reactivity of a Natural Product, Zerumbone

Zerumbone is a cyclic seaquiterpene and, a potential resource for natural materials-related diversity-oriented synthesis (NMRDOS). Zerumbone, the main component of the essential oil of a wild ginger, Zingiber zerumbet Smith, showed strong reactivity with good chemo-, regio-, and stereoselectivity. To build the foundations for the industrial use of zerumbone, we examined conjugate addition, transannular reactions, ring cleavage, ring expansion, and asymmetric induction. The biological activity of zerumbone derivatives was also studied.

Targeting protein homodimerization: A novel drug discovery system

To identify a novel class of antibiotics, we have developed a high‐throughput genetic system for targeting the homodimerization (HD system) of histidine kinase (HK), which is essential for a bacterial signal transduction system (two‐component system, TCS). By using the HD system, we screened a chemical library and identified a compound, I‐8‐15 (1‐dodecyl‐2‐isopropylimidazole), that specifically inhibited the dimerization of HK encoded by the YycG gene of Staphylococcus aureus and induced concomitant bacterial cell death. I‐8‐15 also showed antibacterial activity against MRSA (methicillin‐resistant S. aureus) and VRE (vancomycin‐resistant Enterococcus faecalis) with MICs at 25 and 50 μg/ml, respectively.

Asymmetric syntheses of nitroalkanols using Pseudomonas sp. lipase: a proposal for the selection of the solvent system of lipase-catalyzed transesterification

Abstract By lipase-catalyzed stereoselective transesterification using Amano AK from Pseudomonas sp., nitroalcohols such as 1-nitro-2-butanol and 1-nitro-3-methyl-2-butanol were synthesized enantioselectively with enantiomeric ratios ( E values) of 20.9 and 12.5, respectively, in n -propyl ether. Various results were obtained during the lipase-catalyzed transesterification by changing the organic solvents that were used. The plots of the E values against the reciprocal of the dielectric constants ( e ) of the various organic solvents produced a bell-shaped curve which had a maximum E value for n -propyl ether (1/ e =0.3). The distance between the enzyme and the substrate might be changed in response to a change in the organic solvent.

The chemistry of zerumbone. Part 3: Stereospecific creation of five stereogenic centers by double Sharpless oxidation

Abstract The Sharpless asymmetric epoxidation was applied to zerumbol 2 in order to introduce chirality into the readily available achiral sesquiterpene zerumbone 1. Single bisepoxides (+)-3 and (−)-3 were obtained in nearly 100% enantiomeric purity, characterized as the unexpected all erythro configuration by X-ray analysis.

Sedative Effects of Inhaled Benzylacetone and Structural Features Contributing to Its Activity

Benzylacetone is released by heated agarwood, when inhaled it has a potent effect on reducing the locomotor activity of mice. This study investigated the relationships between the sedative activities of benzylacetone and its derivatives as well as the chemical structures of these compounds by comparing their activities in mice treated with a series of compounds. It was demonstrated that benzylacetone-like compounds had sedative activities and their intensities varied depending on the functional group in the carbon chain, the substituent in the benzene ring, and their combinations. A quantitative structure-activity relationship study was carried out using a series of 17 benzylacetone derivatives to determine the structural features with significant for the sedative activity.

Isolation of hemicellulose from a sorghum, Andropogon sorghum Brot, Kumadake no. 263, and determination of its constituent sugars.

Hemicellulose was isolated from the stem of sorghum, Andropogon sorghum Brot, Kumadake no. 263, and the constituent sugars of this isolate were determined. The xylose concentration in the hemicellulose of SV263 was extremely high.

Piperine analogs in a hydrophobic fraction from Piper ribersoides (Piperaceae) and its insect antifeedant activity

Piper ribersoides Wall. (Piperaceae), which is called “Khua Sa khan” in the local language, is mainly grown in Laos. This plant is used as a food in Laos, but no report on its metabolites exists. Crushed stems were immersed in methanol. The ethyl acetate fraction showed potential insect antifeedant activity for Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae), and some of the active compounds were piperine analogs. Piperine and its geometrical isomer independently showed potent antifeedant activities, and piperine was presumably the main active compound in the methanol extract. Interestingly, we discovered that the antifeedant activity was reduced when they were mixed (50:50).