Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Volume 63 , Issue 6
Showing 1-13 articles out of 13 articles from the selected issue
Review
  • Yoshihiro Oonishi
    2015 Volume 63 Issue 6 Pages 397-407
    Published: June 01, 2015
    Released: June 01, 2015
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    Novel Rh(I)-catalyzed cyclizations through a different type of rhodacycle intermediate which is formed by hydroacylation of 4,6-dienal or oxidative addition of diene and alkene are described. Hydroacylation of 4,6-dienal afforded various 7-membered rings in good to high yields, while cycloisomerization of diene and alkene provided 5- or 6-membered rings in good yields. On the basis of these studies, we have also succeeded in developing the sequential reaction of hydroacylation followed by cycloisomerization to produce bicyclic compounds in a stereoselective manner and thus this reaction was expanded to the synthesis of epiglobulol. Furthermore, both Rh(I)-catalyzed hydroacylation and cycloisomerization using ionic liquid (IL) as a solvent were investigated and it was found that the IL recovered after the reaction, which contains the Rh(I) catalyst, could be recycled several times without loss of catalytic activity.
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Regular Articles
  • Suparna Sacchit Bakhle, Jasmine Gev Avari
    2015 Volume 63 Issue 6 Pages 408-417
    Published: June 01, 2015
    Released: June 01, 2015
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    The present investigations highlight the development of solid self-emulsifying drug delivery system (solid-SEDDS) for improved oral delivery of the poorly water-soluble drug; cilnidipine. Liquid SEDDS of the drug were formulated using Capryol 90 as the oil phase, Tween 80 as the surfactant, and Transcutol HP as the co-surfactant after screening various vehicles. The prepared systems were characterized for self-emulsification time, robustness to dilution, % transmittance, globule size, drug release, and thermodynamic stability. Ternary phase diagrams were plotted to identify the area of microemulsification. The optimized liquid SEDDS was transformed into a free-flowing powder using Neusilin US2 as the adsorbent. Solid self-emulsifying powder retained the self-emulsifying property of the liquid SEDDS. Differential scanning calorimetric, X-ray powder diffraction studies revealed the possibility of transformation of the crystalline form of the drug to the amorphous form in the SEDDS prepared with the carrier. The morphology of solid-SEDDS from scanning electron microscopy studies demonstrated the presence of spherical, granular particles indicating good flowing ability. Dissolution studies revealed enhanced dissolution of the drug from the solid system compared with the pure drug and its marketed formulation. Similarly, the in vitro absorption profile of the drug from the formulated SEDDS was significantly higher compared with pure drug. Thus it can be concluded that solid-SEDDS, amenable for development of solid dosage form, can be successfully developed using Neusilin US2 with the potential of enhancing the solubility, dissolution rate, and bioavailability of the drug.
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  • Kazuhiro Takeguchi, Yutaka Hirakura, Kouji Yamazaki, Itsuro Shimada, S ...
    2015 Volume 63 Issue 6 Pages 418-422
    Published: June 01, 2015
    Released: June 01, 2015
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    ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed in Astellas Pharma Inc. as a novel and selective inhibitor of the fusion protein EML4-ALK. We investigated the thermodynamic stability of five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) in detail. To determine the most stable form at ambient temperature, powder X-ray diffraction, differential scanning calorimetry, and solubility measurements were conducted. Of the five polymorphs, A04 was the most stable and A05 was the least stable. The relationship between A04 and A03 and A04 and A01 were mutually monotropic, while that between A01 and A02 was enantiotropic. The transition temperature from A02 to A01 was estimated as 325 K. A02 was more thermodynamically stable at ambient temperature than A01. Furthermore, the method to estimate polymorphic transition temperatures using solution calorimetry was found to be effective. The systematic characterization of ASP3026 polymorphs presented in this study enables the selective crystallization of the most stable form and design of solid formulations.
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  • Kyu-Mok Hwang, Shin-Ae Park, Ju-Young Kim, Chun-Woong Park, Yun-Seok R ...
    2015 Volume 63 Issue 6 Pages 423-430
    Published: June 01, 2015
    Released: June 01, 2015
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    This paper focuses on the development and physicochemical characterization of a self-microemulsifying drug delivery system (SMEDDS) containing a fixed-dose combination of atorvastatin (ATR) and ezetimibe (EZT). The solubility of both drugs was determined in excipient screening studies. Ternary-phase diagrams were drawn for 27 systems composed of different surfactants, cosurfactants, and oils at different surfactant-to-cosurfactant (S/CoS) ratios, and the system exhibiting the largest percentage area of the self-microemulsifying region was selected. The optimum oil ratio in the SMEDDS was selected by evaluating the mean droplet size of the resultant microemulsions. The underlying mechanism of the lower ATR loading capacity compared with EZT was elucidated by measurement of the zeta potential and UV absorption analysis. The results implied that ATR was located exclusively in the surfactant–cosurfactant layer, whereas EZT was located both in the microemulsion core and the surfactant–cosurfactant layer. In vitro dissolution studies showed that the SMEDDS had higher initial dissolution rates for both drugs when compared with marketed products. More importantly, EZT had a significantly increased dissolution profile in distilled water and pH 4.0 acetate buffer, implying enhanced bioavailability.
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  • Fen Jing, Xiaoyun Fu, Sha Li, Baolin Li, Jijun Zhao, Xuefeng Wang, Yum ...
    2015 Volume 63 Issue 6 Pages 431-437
    Published: June 01, 2015
    Released: June 01, 2015
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    Novel hybrids from 1,3,4-thiadiazole and benzisoselenazolone were designed, synthesized and evaluated for their in vitro antiproliferative activities by CCK-8 assay against three types of human cancer cell lines, SMMC-7721, MCF-7 and A549 cells. The preliminary bioassay results demonstrated that all tested compounds 4a–p showed potent antiproliferative activities, and some compounds exhibited better effects than positive control ethaselen and 5-fluorouracil (5-FU) against various cancer cell lines. Furthermore, compound 4g showed significant antiproliferative activities against SMMC-7721 cells with an IC50 value of 2.08 µM. Compounds 4b and 4m displayed highly effective biological activities against MCF-7 cells with an IC50 values of 2.03 and 2.06 µM, respectively. Compound 4i exhibited the best inhibitory effect against A549 cells with an IC50 value of 1.03 µM.
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  • Guang-fei Wang, Rui-hua Ji, Meng-xue Cao, Wei-zhuo Tang, Hao-bing Yu, ...
    2015 Volume 63 Issue 6 Pages 438-442
    Published: June 01, 2015
    Released: June 01, 2015
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    Chemical investigation on CH2Cl2 extract of the marine sponge Diacarnus megaspinorhabdosa resulted in the isolation of two new farnesylacetone derivatives 12, a new γ-lactone 3, a known dinorditerpenone 4 and four known norsesterterpene peroxides 58. Their structures were elucidated by using one and two dimensional (1D and 2D)-NMR, high resolution-electrospray ionization (HR-ESI)-MS, and comparison with the literature. Compounds 1 and 2 were cis/trans-olefinic isomers and determined through nuclear Overhauser effect spectroscopy (NOESY) experiment. The absolute configuration of 3 was established by comparison of circular dichroism (CD) data with known lactones. The cytotoxic activities of the compounds were evaluated against five cancer cell lines, and compound 3 showed moderate cytotoxicity activities against cancer cell lines HeLa, H446, NCI-H460, SGC-7901 and MCF-7, with IC50 values in the range of 18.5 to 47.1 µM.
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  • Miriam F. Ayad, N. Magdy
    2015 Volume 63 Issue 6 Pages 443-449
    Published: June 01, 2015
    Released: June 01, 2015
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    Two accurate, reliable, and highly sensitive spectrofluorometric methods were developed for simultaneous determination of the binary mixture of Atorvastatin and Ezetimibe without prior separation steps. The first method is based on double scan synchronous fluorescence spectrometry. Each of Atorvastatin and Ezetimibe can be determined independent of the other when scanned at Δλ=100 nm and 40 nm, respectively. The relative fluorescence intensity–concentration plots at two wavelengths, 272 (Δλ=100 nm) and 266 nm (Δλ=40 nm) were rectilinear over the range of 0.4–8 µg/mL (for Atorvastatin) and 0.6–8 µg/mL (for Ezetimibe), respectively. The second method is based on the technique of simultaneous equations (Vierodt’s method), in which two equations are solved simultaneously after using a single excitation wavelength of 273 nm and λEm1=380 nm of Atorvastatin and λEm2=301 nm of Ezetimibe. Under the optimum conditions, linear relationships were found between the relative fluorescence intensity and the concentrations of the investigated drugs in the range of 0.4–8 µg/mL (for Atorvastatin) 0.6–8 µg/mL (for Ezetimibe). The different experimental parameters affecting the fluorescence intensities of the two drugs were carefully studied and optimized. The proposed methods were successfully applied for the determination of the investigated drugs in pure form, dosage form and in synthetic mixtures with good recovery and the results obtained were favorably compared to those obtained with a reference method.
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  • Magdy Mohamed Hemdan, Heba Kamal Abd El-Mawgoude
    2015 Volume 63 Issue 6 Pages 450-456
    Published: June 01, 2015
    Released: June 01, 2015
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    The reaction of lauroyl isothiocyanate and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was used to synthesize the title compound 2. Compound 2 could serve as the main building block in the synthesis of many target heterocyclic systems. Various fused pyrimidines were synthesized in the reactions of compound 2 with sodium ethoxide, hydrazine hydrate, phenyl hydrazine, ethyl carbazate, thiourea, and/or 2-aminothiophenol. The structures of the synthesized compounds were confirmed by microanalytical and spectral data.
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  • Yoshinori Onuki, Yoshiaki Machida, Takashi Yokawa, Chieko Seike, Shota ...
    2015 Volume 63 Issue 6 Pages 457-462
    Published: June 01, 2015
    Released: June 01, 2015
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    A cream that contains menthol and diphenhydramine is widely prepared in hospital pharmacies and prescribed to patients for the treatment of pruritus associated with chronic kidney disease. However, there is a serious concern regarding its physical stability; therefore, we investigated this issue using magnetic resonance imaging (MRI). For a sample preparation, a menthol-containing ethanol solution was mixed with a commercial diphenhydramine cream. After storage for 7 d at 40°C, substantial phase separation into two distinct layers (upper and lower layers) was observed in the sample. This study further examined the components of the phase-separated layers using magnetic resonance (MR) spectroscopy and chemical shift selective images, and it was verified that the upper layer consisted of packed oil droplet layers, whereas the lower was an aqueous phase. Subsequently, the time-dependent phase separation of the sample at different temperatures was investigated. From the MR images, including a T2 relaxation time map and apparent diffusion coefficient maps, it was obvious that the phase separation developed further with increasing temperature; the most substantial phase separation was observed from the sample stored at 40°C, while no phase separation was detected at 25°C. In the final phase of this study, we conducted a formulation study and succeeded in improving the cream’s physical stability by adding a hydrophilic surfactant to the preparation.
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  • Hikaru Abe, Chiharu Sakashita, Manabu Kawada, Akio Nomoto, Takumi Wata ...
    2015 Volume 63 Issue 6 Pages 463-468
    Published: June 01, 2015
    Released: June 01, 2015
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    The total synthesis of NBRI16716B (2), a naturally occurring modulator of tumor–stroma interactions, was successfully achieved. Using this synthetic route, a dehydroxy analogue (21) and a derivative lacking the 5-hydroxy-3-methylpentenoyl side chain (22) became accessible. A preliminary structure–activity relationship study to unveil the structural requirements for selective inhibition of tumor cells cocultured with stromal cells revealed that both of the hydroxamate structures of 2 are indispensable, whereas the 5-hydroxy-3-methylpentenoyl side chain is not essential.
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  • Adeyemi Francis Gabriel, Zhen Li, Ryouhei Kusuda, Chiaki Tanaka, Tomof ...
    2015 Volume 63 Issue 6 Pages 469-475
    Published: June 01, 2015
    Released: June 01, 2015
    [Advance publication] Released: April 09, 2015
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    Six new polyacetylenic alcohols, termed strongylotriols A and B; pellynols J, K, and L; and isopellynol A, together with three known polyacetylenic alcohols, pellynols A, B, and C were isolated from the marine sponges Petrosia sp., and Halichondria sp. collected in Okinawa, Japan. Their planer structures were determined based on 2D-NMR and mass spectrometric analysis of the degraded products by RuCl3 oxidation. The absolute stereochemistry of isolates was examined by their Mosher’s esters. The strongylotriols were found to be optically pure compounds, whereas the pellynols are diastereomeric mixtures at the C-6 position. Proliferation experiments using the HeLa and K562 cell lines suggested that the essential structural units for activity are the “hexa-2,4-diyn-1,6-diol” and “pent-1-en-4-yn-3-ol” on the termini.
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Notes
  • Hiromichi Asamoto, Yasuhito Nobushi, Takahiko Oi, Kazuo Uchikura
    2015 Volume 63 Issue 6 Pages 476-480
    Published: June 01, 2015
    Released: June 01, 2015
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    We have developed a highly sensitive, simple method for the quantitative determination of miglitol in standard serum samples using column-switching ion-pair HPLC with tris(2,2′-bipyridine)ruthenium(II)-electrogenerated chemiluminescence detection. The serum samples were directly injected into a column-switching HPLC system with a Shim-pack MAYI-SCX precolumn to remove the serum matrix. Chromatographic separation of miglitol was achieved on a TSKgel ODS 100-V column using a mobile phase containing sodium 1-octanesulfonate as an ion-pair reagent. The detection and quantification limits of miglitol were 3 and 10 ng/mL, respectively. The calibration curve for miglitol in the serum samples showed good linearity (r2=0.9997) in the range of 10–2500 ng/mL. The recovery rate of miglitol from the serum samples was more than 94% as calculated from blank serum samples spiked with miglitol 50, 100, 500, 1000, and 2000 ng/mL. Therefore, this method can be applied to routine therapeutic monitoring of miglitol in serum samples.
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  • Le Son Hoang, Manh Hung Tran, Joo Sang Lee, Dao Cuong To, Van Thu Nguy ...
    2015 Volume 63 Issue 6 Pages 481-484
    Published: June 01, 2015
    Released: June 01, 2015
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    A novel pyrrolizidine alkaloids, madhumidine A (1), and two known alkaloids, lindelofidine benzoic acid ester (2) and minalobine B (3) were isolated from the leaves of Madhuca pasquieri (Dubard) H. J. LAM. The chemical structures of these alkaloids were established mainly by NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against lipopolysaccharide-induced nitric oxide production in macrophage RAW264.7 cell. In addition, the cytotoxic activity of all isolated compounds was tested against a panel of cancer cell lines.
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