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Volume 60, Issue 3
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Review
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Masahiro YoshidaArticle type: Review
2012 Volume 60 Issue 3 Pages 285-299
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSIt is known that propargylic compounds having an ester and a halide at the propargylic positions react with palladium complexes leading to π-propargylpalladium and allenylpalladium complexes, which cause various transformations in the presence of the reactants. The aim of the present study was to develop novel palladium-catalyzed transformations using propargylic compounds. As diastereoselective reactions of propargylic compounds with bis-nucleophiles, we have developed palladium-catalyzed reactions of propargylic carbonates with 2-substituted cyclohexane-1,3-diones, 2-(2-hydroxyphenyl)acetates and 2-oxocyclohex-3-enecarboxylates. These processes produce highly substituted cyclic compounds in a highly stereoselective manner. Through our studies on the construction of substituted 2,3-allenols by the reactions of propargylic oxiranes, it has been made clear that palladium-catalyzed coupling reactions occur in the presence of arylboronic acids and terminal alkynes. The processes can be carried out in mild conditions to yield substituted 4-aryl-2,3-allenols in a diastereoselective manner. In our attempt to develop CO2-recycling reactions, we developed a methodology for the synthesis of cyclic carbonates by palladium-catalyzed reactions of propargylic carbonates with phenols. Our findings suggested that the process proceeds through a pathway involving decarboxylation-followed fixation of the liberated CO2. Diastereoselective, enantioselective, and enantiospecific construction of cyclic carbonates have been achieved by the application of this methodology.View full abstractDownload PDF (2687K)
Regular Articles
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Akinori Nakamura, Daisuke Mori, Kakuji TojoArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 300-305
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSWe proposed an in vitro/in vivo/in silico method for evaluating the clinical performance of matrix type transdermal therapeutic systems (TTSs). This method is based on the following four approaches: (1) drug release experiment, (2) in vitro penetration experiment using excised hairless mouse skin, (3) clinical pharmacokinetic study, and (4) mathematical model for evaluating the pharmacokinetic profile. The tulobuterol TTS was used as an example of a matrix type TTS in this study. The drug diffusion coefficient in the matrix device was calculated from the result of the release experiment. The drug diffusion coefficient and the partition coefficient in the skin were calculated from the results of in vitro skin penetration experiments where hairless mice and rats were used. Those parameters were used as substitutes of human. Further, these parameters were used for solving the governing partial differential equation on skin penetration. The time profiles of the serum concentration in human after applying the tulobuterol TTS were predicted and compared with the clinical data. The predicted profiles obtained from the data of hairless mice reproduced the influence of drug depletion adequately and well agreed with the clinical data, while those from the data of rats differed clearly in the initial rise. This method is useful for prediction of pharmacokinetic profiles of TTSs.View full abstractDownload PDF (577K) -
Hyun Jung Shin, So Young Lee, Ju Sun Kim, Sanghyun Lee, Ran Joo Choi, ...Article type: Regular Article
2012 Volume 60 Issue 3 Pages 306-314
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSSix new germacranolides, zawadskinolides A—F (1—6), and a new eudesmane glucoside, chrysantiloboside (7) were isolated from the aerial parts of Dendranthema zawadskii var. latilobum, along with thirteen known constituents. Their structures were elucidated by means of spectroscopic evidence. Bioassay showed that flavonoids such as apigenin (9), (−)-eriodictyol (10) and nepetin (12), as well as the sesquiterpene lactone, zawadskinolide F (6), inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells with IC50 values of 66.15, 132.55, 35.44, and 91.32 μM, respectively.View full abstractDownload PDF (755K) -
Takeshi Sugiura, Shinya Uchida, Noriyuki NamikiArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 315-319
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSOrally disintegrating tablets (ODTs) are useful for improving benefits for patients of various ages. Masking the unpleasant taste of a drug is an important factor in the compliance of patients who take ODTs. We evaluated the taste acceptability effects of various taste-masking methods on bitter famotidine ODTs as a clinical pharmacological study. The following methods were tested to compare taste-masking effects: physical masking by spray-coating famotidine with ethyl cellulose versus organoleptic masking with added sweetener and flavor. The ODT samples were prepared as single or combinations of each taste-masking method using a novel suspension spray-coating method including a placebo. A total of 31 healthy volunteers were enrolled in this randomized, double-blind study and asked to score their bitterness, sweetness and total palate impressions by 100 mm visual analogue scale (VAS). VAS scores were significantly improved by the physical and organoleptic methods as compared to without taste-masked ODTs. Furthermore, the combination of both taste-masking methods was most effective for improving palatability and VAS scores were similar to those of placebo ODTs. The results of this study suggest that different taste-masking mechanisms function cooperatively.View full abstractDownload PDF (679K) -
Akiko Ohno, Toru Kawanishi, Haruhiro Okuda, Kiyoshi FukuharaArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 320-324
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSMost of the active components of polypeptides have a complex molecular structure, large molecular size. Such components may also be structurally heterogeneous. Therefore, development of a method that can confirm the consistency of polypeptides amino-acid sequences for product characterization is desirable. In general, it is extremely difficult to distinguish differences of a few amino acid residues in the 1H-NMR spectrum of polypeptides with molecular weights greater than several thousand. However, we have been able to distinguish between three insulin species differing in one to three amino acid residues using a combination of multivariate statistics and 1H-NMR spectra. These results demonstrate that this methodology could be useful for characterization of polypeptides.View full abstractDownload PDF (846K) -
Shohei Sugimoto, Toshiyuki Niwa, Yasuo Nakanishi, Kazumi DanjoArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 325-333
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSA novel ultra-cryo milling micronization technique for pharmaceutical powders using liquid nitrogen (LN2 milling) was used to grind phenytoin, a poorly water-soluble drug, to improve its dissolution rate. LN2 milling produced particles that were much finer and more uniform in size and shape than particles produced by jet milling. However, the dissolution rate of LN2-milled phenytoin was the same as that of unground phenytoin due to agglomeration of the submicron particles. To overcome this, phenytoin was co-ground with polyvinylpyrrolidone (PVP). The dissolution rate of co-ground phenytoin was much higher than that of original phenytoin, single-ground phenytoin, a physical mixture of phenytoin and PVP, or jet-milled phenytoin. X-Ray diffraction showed that the crystalline state of mixtures co-ground by LN2 milling remained unchanged. The equivalent improvement in dissolution, whether phenytoin was co-ground or separately ground and then mixed with PVP, suggested that even when co-ground, the grinding of PVP and phenytoin occurs essentially independently. Mixing original PVP with ground phenytoin provided a slight improvement in dissolution, indicating that the particle size of PVP is important for improving dissolution. When mixed with ground phenytoin, PVP ground by LN2 milling aided the wettability and dispersion of phenytoin, enhancing utilization of the large surface area of ground phenytoin. Co-grinding phenytoin with other excipients such as Eudragit L100, hypromellose, hypromellose acetate-succinate, microcrystalline cellulose, hydroxypropylcellulose and carboxymethyl cellulose also improved the dissolution profile, indicating an ultra-cryo milling and co-grinding technique in liquid nitrogen has a broad applicability of the dissolution enhancement of phenytoin.View full abstractDownload PDF (3466K) -
Daiki Hira, Tomoyuki Okuda, Mika Ichihashi, Haruyoshi Kojima, Hirokazu ...Article type: Regular Article
2012 Volume 60 Issue 3 Pages 334-340
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSWhile dry powder inhalations are commonly used to treat pulmonary diseases, their clinical performance depends on patient inspiratory flow patterns. The purpose of this study was to develop a new powder with high and stable therapeutic performance for various patients. We applied the supercritical antisolvent (SCF) method to salbutamol sulfate (SS) to prepare a bulky SS particle (SS-SCF). Tests of in vitro inhalation performance with a human inspiratory flow simulator revealed SS-SCF to be less susceptible to inspiratory flow patterns than milled SS. When inspired, the unique structure seemed to be broken resulting in small fragments that could be delivered to the lungs. However, stability tests under physical stress showed tolerance for transportation and handling. In addition, optimization of the concentration of the SS solution applied to SCF method improved the in vitro inhalation performance of SS-SCF. These results indicated that a unique bulky SS powder prepared by the SCF method was useful for dry powder inhalation.View full abstractDownload PDF (5091K) -
Daiki Hira, Tomoyuki Okuda, Mika Ichihashi, Ayano Mizutani, Kazunori I ...Article type: Regular Article
2012 Volume 60 Issue 3 Pages 341-347
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSThe aim of this study was to reveal the relationship between human inspiratory flow patterns and the concomitant drops in pressure in different inhalation devices, and the influence of the devices on inhalation performance. As a model formulation for inhalers, a physically mixed dry powder composed of salbutamol sulfate and coarse lactose monohydrate was selected. The drops in pressure at 28.3 L/min of three inhalation devices, Single-type, Dual-type, and Reverse-type, was 1.0, 5.1, and 8.7 kPa, respectively. Measurements of human inspiratory patterns revealed that although the least resistant device (Single) had large inter- and intra-individual variation of peak flow rate (PFR), the coefficients of variation of PFR of the three devices were almost the same. In tests with a human inspiratory flow simulator in vitro, inhalation performance was higher, but the variation in inhalation performance in the range of human flow patterns was wider, for the more resistant device. To minimize the intra- and inter-individual variation in inhalation performance for the model formulation in this study, a formulation design that allows active pharmaceutical ingredient to detach from the carrier with a lower inhalation flow rate is needed.View full abstractDownload PDF (1931K) -
Sakura Yoshida, Mamoru Haratake, Takeshi Fuchigami, Morio NakayamaArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 348-353
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSFish are selenium rich foodstuffs and a major selenium source for the Japanese population. Niboshi is processed from Japanese anchovy (Engraulis japonicus) and commonly used to prepare soup stock for Japanese dishes. In this study, we characterized selenium species in the Niboshi extract by ultrafiltration, ion-exchange chromatography and mass spectrometry. Selenium species in the Niboshi were more extractable by polar solvents (water and ethanol) than an apolar one (hexane) along with amino acids and proteinous species. Selenium in the water-extract from the Niboshi was mostly ascribed to organoselenium compounds with a molecular mass less than 5 kDa. Although selenoamino acids and selenoproteins and their fragments were involved in the extract, a large portion of the selenium species appeared to be low-molecular-mass organoselenium compounds other than selenoamino acids and their derivatives. Ion-exchange chromatographic separations revealed that most of the selenium species in the extract possess anionic and/or amphoteric characteristics. One of these selenium species from the Niboshi extract was detected at m/z 577 for 80Se by mass spectrometry subsequent to ion-pair extraction.View full abstractDownload PDF (505K) -
Kouichi Yoshizaki, Shoji YaharaArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 354-362
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSSeven new dammarane-type triterpenoid saponins, chikusetsusaponin FK1 (1), chikusetsusaponin FK2 (2), chikusetsusaponin FK3 (3), chikusetsusaponin FK4 (4), chikusetsusaponin FK5 (5), chikusetsusaponin FK6 (6), and chikusetsusaponin FK7 (7), and eleven known triterpenoid saponins, ginsenoside Rb3 (9), ginsenoside Rc (10), chikusetsusaponin VI (11), ginsenoside Re (12), ginsenoside Rg1 (13), pseudo-ginsenoside RS1 (14), notoginsenoside R1 (15), chikusetsusaponin L5 (17), chikusetsusaponin L10 (18), chikusetsusaponin IVa (19), and chikusetsusaponin V (20), were isolated from the fruits of Panax japonicus C. A. MEYER, collected in Kumamoto prefecture, Japan, and two new dammarane-type triterpenoid saponin, chikusetsusaponin FK5 (5) and chikusetsusaponin FM1 (8), and five known triterpenoid saponins, ginsenoside Rb3 (9), ginsenoside Rc (10), ginsenoside Re (12), ginsenoside Rg1 (13), and floralquinquenoside E (16), were isolated from the fruits of P. japonicus C. A. MEYER, collected in Miyazaki prefecture, Japan. The structures of new chikusetsusaponins were elucidated on the basis of chemical and physicochemical evidences.View full abstractDownload PDF (981K) -
Mohamed-Elamir F. Hegazy, Hisashi Matsuda, Seikou Nakamura, Mikuko Yab ...Article type: Regular Article
2012 Volume 60 Issue 3 Pages 363-370
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSThe methylene chloride–methanol (1 : 1) extract from the air-dried aerial parts of wild Pulicaria undulata collected in North Sinia, Egypt, showed inhibitory effects on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) in RAW264.7 macrophages. From the extract, three new sesquiterpenes named 5α-hydroperoxyivalin, 8-epi-xanthanol, and 8-epi-isoxanthanol were isolated together with four known sesquiterpenes. The structure of each new sesquiterpenes was determined on the basis of physicochemical and chemical evidence. In addition, all the sesquiterpenoids significantly inhibited the production of NO. Ivalin (IC50=2.0 μM) and 2α-hydroxyalantolactone (1.8 μM) showed particularly strong inhibitory effects, but had strong cytotoxic effects as well. Furthermore, ivalin and 2α-hydroxyalantolactone concentration-dependently reduced inducible NO synthase (iNOS) protein levels in RAW264.7 cells.View full abstractDownload PDF (945K) -
Atsushi Sekiya, Shinya Oishi, Nobutaka Fujii, Takaki KoideArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 371-376
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSSafer heparin-neutralizing agents are currently required to replace protamine, the use of which causes adverse effects such as anaphylaxia. Low-molecular-weight (LMW) heparin mimetics that potentiate antithrombin III (AT) action are also valuable as anti-thrombotics. This paper describes a high-throughput assay for both heparin-neutralizing agents and LMW heparin mimetics without the use of blood preparations. The assay is based on turbidimetric measurement of a solution of collagen, heparin, and a test compound. Native collagen molecules spontaneously form insoluble fibrils when transferred to a physiological buffer, and this process is inhibited by heparin. In the presence of a heparin-neutralizing agent or an LMW heparin mimetic, the inhibitory effect of heparin is canceled and turbidity increase is retrieved. We demonstrated that this assay is effective in detecting potential agents with high reliability (Z′ factor=0.9). The screening of a chemical library (34400 compounds) was further performed in a 384-well format, and led to the identification of a novel heparin-neutralizing agent. Since this assay protocol is feasible for an automated high-throughput screening (HTS) system, it could enhance the lead seeking process for drugs related to heparin/heparan sulfate (HS) functions.View full abstractDownload PDF (1055K) -
Noriaki Fukuyama, Masaaki Shibuya, Yutaka OriharaArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 377-380
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSTwo new polyacetylenes, 1-hydroxydihydropanaxacol (3) and 17-hydroxypanaxacol (4), were isolated from Panax ginseng hairy root culture, along with dihydropanaxacol (1), panaxacol (2) and ginsenoyne D (5). Highly hydroxylated compounds 1—4 were isolated from the medium and compound 5, which was a biosynthetic precursor of compound 1, was isolated from the roots. Compounds 1—4 showed antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Cryptococcus neoformans and Aspergillus fumigatus. It is suggested that P. ginseng plants release antimicrobial polyacetylenes into the surrounding soil from the roots as defense compounds.View full abstractDownload PDF (425K) -
Fuyuhiko Inagaki, Harumi Kobayashi, Chisato MukaiArticle type: Regular Article
2012 Volume 60 Issue 3 Pages 381-384
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSThe regioselective intramolecular 1,3-dipolar cycloaddition of the phenylsulfonylallene-nitrone derivatives has been developed. This reaction showed that the distal double bond of the allene exclusively reacted with the nitrone group to produce the bicyclic isoxazolidine derivatives regardless of the substitution pattern on the allenyl moiety.View full abstractDownload PDF (612K)
Notes
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Suwen Hu, Siyun Nian, Kuiyou Qin, Tong Xiao, Lingna Li, Xiaolu Qi, Faq ...Article type: Note
2012 Volume 60 Issue 3 Pages 385-390
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSThe design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3′ may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson’s disease.View full abstractDownload PDF (561K) -
Rapid and Sensitive Method for Measuring the Plasma Concentration of Doxorubicin and Its MetabolitesKumiko Sakai-Kato, Kunie Nanjo, Toru Kawanishi, Haruhiro OkudaArticle type: Note
2012 Volume 60 Issue 3 Pages 391-396
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSDoxorubicin is an anti-cancer drug with a wide therapeutic range. However, it and its metabolites cause severe side effects, limiting its clinical use. Therefore, measuring the plasma concentration of doxorubicin and its metabolites is important to study the dosing regimen of doxorubicin. We developed a rapid and sensitive method by ultra-high-performance liquid chromatography with fluorescent detection for measuring the plasma concentration of doxorubicin and its metabolites in small volumes (around 10 μL), enabling repeated measurements from the same mouse. The sensitivity of 7-deoxydoxorubicinolone, a major metabolite of doxorubicin, increased about 5 times than those ever reported using conventional HPLC, and the run time was within 3 min. The area under the curve (AUC0—24 h) of doxorubicin was 5.9 μg h/mL similar to the value of 4.16 μg h/mL obtained previously using a conventional HPLC method. This method would provide information that could be used to refine the therapeutic approach to doxorubicin use.View full abstractDownload PDF (711K) -
Megumi Furukawa, Naoki Oikawa, Toru Imohata, Mitsuko Makino, Shoujiro ...Article type: Note
2012 Volume 60 Issue 3 Pages 397-401
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSThree new monoterpene glucosides, ziziphoroside A (1), B (2), and C (3), together with fifteen known compounds were isolated from the whole herb of Z. clinopodioides. The structures of new compounds were determined primarily from 1D-, 2D-NMR and circular dichroism (CD) spectroscopic analyses. The isolated compounds were evaluated for their inhibitory activity against nitric oxide (NO) production by lipopolysaccharide (LPS) and interferon (IFN)-γ activated macrophages, RAW 264.7. Shizonepetoside A (8) and flavones (11, 12, 13) showed potent inhibitory activity against NO production.View full abstractDownload PDF (658K) -
Bahaa Gamal Mohamed Youssif, Kensuke Okuda, Tetsuya Kadonosono, Ola Ib ...Article type: Note
2012 Volume 60 Issue 3 Pages 402-407
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSA near-infrared fluorochrome, GPU-311, was designed, synthesized and evaluated for its application in non-invasive imaging of tumor hypoxia. Efficient synthesis was achieved by nucleophilic substitution and click chemistry ring using the bifunctional tetraethylene glycol linker 2 containing thiol and azide groups for the conjugation of the propargylated nitroimidazole 1 and the heptamethine cyanine dye 3 bearing a 2-chloro-1-cyclohexenyl ring. GPU-311 exhibited long excitation and emission wavelength (Ex/Em=785/802 nm) and a decent quantum yield (0.05). The water solubility and hydrophilicity of GPU-311 increased. After in vitro treatment of SUIT-2/HRE-Luc pancreatic cancer cells with GPU-311, a higher level of fluorescence was observed selectively in hypoxia than in normoxia. However, in vivo fluorescence imaging of a mouse xenograft model after GPU-311 administration revealed inadequate accumulation of GPU-311 in tumors due to its rapid elimination through the liver.View full abstractDownload PDF (1390K) -
Nobuko Mibu, Kazumi Yokomizo, Wataru Uchida, Satoshi Takemura, Jianron ...Article type: Note
2012 Volume 60 Issue 3 Pages 408-414
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSIn terms of molecular symmetry and bioactivity, new C3- and CS-symmetrical derivatives based on the tris(2-aminoethyl)amine scaffold were designed and synthesized. The synthesized compounds were evaluated for antiviral activity with herpes simplex virus type 1 (HSV-1) by a plaque reduction assay and for cytotoxic activity with Vero cells. Most of the compounds showed no significant anti-HSV-1 activity, but some of the symmetrical derivatives showed high levels of cytotoxic activitiy.View full abstractDownload PDF (608K) -
Feng Gao, Min Yu, Qiao-Hong Chen, Feng-Peng WangArticle type: Note
2012 Volume 60 Issue 3 Pages 415-418
Published: March 01, 2012
Released on J-STAGE: March 01, 2012
JOURNAL FREE ACCESSA selective intramolecular transacylation from C-4 to C-5 of taxoids, which occurred simultaneously with the oxetane D-ring opening and was promoted by TiCl4, was presented. The optimal condition was found to be treatment of substrates in double dose of dichloromethane (per mg of substrate dissolved in 2 mL DCM) with 1 eq of TiCl4 at 25°C for 10 min.View full abstractDownload PDF (494K)
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