Chemical & pharmaceutical bulletin (Chem Pharmaceut Bull)

Publications in this journal

• Article: Synthesis and antiproliferative effect of novel curcumin analogues.

  Bingmi Liu, Mingyu Xia, Xiaoling Ji, Liying Xu, Jinhua Dong
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  ABSTRACT: Novel curcumin analogues with α,β-unsaturated ketone moiety and/or α,β-saturated ketone structure were synthesized from curcumin via alkylation at the central carbon and the phenolic hydroxy groups, and hydrogenation of α,β-unsaturated ketone moiety. The antiproliferative activities were tested in five human solid tumor cell lines in vitro. Most of the compounds exhibited increased antiproliferative activities comparing with that of curcumin. Structure-activity relationship (SAR) analysis revealed that the α,β-unsaturated ketone structure was not required for antiproliferative activity of these curcumin analogues. Among these compounds, 1,7-bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16f) was the most effective one with IC50 value below 1µM, which was 9- to 81-fold more potent than curcumin.
  Chemical & pharmaceutical bulletin 05/2013;
• Article: Synthesis and in vitro Antifungal Activities of New 2-Aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium Bromides.

  Xinjuan Yang, Yao Yao, Yuyan Qin, Zhe Hou, Rui Yang, Fang Miao, Le Zhou
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  ABSTRACT: 2-Aryl-3,4-dihydroisoquinolin-2-iums might be considered as a class of simple analogues of natural quaternary benzo[c]phenanthridine alkaloids. In this paper, 26 new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides with various substituents in N-aromatic ring were synthesized from commercially available 1,3-benzodioxole in good to excellent yields. All the compounds were elucidated by MS, HRMS, IR, (1)H- and (13)C-NMR analysis, and evaluated for antifungal activities in vitro against Alternaria alternate, Curvularia lunata and Fusarium oxysporum sp. niveum at 50 µg/mL. Most of the compounds showed higher activities against all the test fungi than their natural model compounds sanguinarine and chelerythrine. For A. alternate and Curvularia lunata, most of them were also more active than thiabendazole, a commercial fungicide standard. The structure-activity relationship indicated that the substituent in N-aromatic ring and its position had significant effect on the activity. The general trend was that halogen atoms and CF3 remarkably enhanced the activity while CH3 and OCH3 decreased the activity. Generally, o-substituted isomers were more active than m- and p-substituted isomer. The present results suggest that the title compounds are potential for the development of new isoquinoline antimicrobial agents.
  Chemical & pharmaceutical bulletin 05/2013;
• Article: A Bioluminescent Assay System for Whole-Cell Determination of Hormones.

  Sung Bae Kim, Toshiyuki Suzuki, Akira Kimura
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  ABSTRACT: A bioluminescent-assay system was fabricated for an efficient determination of bioactive small molecules in physiological samples. The following three components were newly created for this assay system: (i) a single-chain probe exerting a 7.2-times stronger optical intensity than conventional ones, (ii) a high throughput assay device uniquely designed for the assay system with ca. one-fourth smaller standard deviation (SD) to samples than without the device, (iii) a buffer cocktail optimized for the assay system. The advantages of the assay system were evaluated by determining (i) the stress hormone levels in human saliva and (ii) multicolor imaging of genomic and nongenomic effects of woman sex hormones. This study guides on how to fabricate an efficient assay system for bioactive small molecules with convenience and high precision.
  Chemical & pharmaceutical bulletin 04/2013;
• Article: Design, synthesis, biological evaluation, and molecular docking studies of quinolone derivatives as potential antitumor topoisomerase I inhibitors.

  Kai-Jun Shou, Jie Li, Yi Jin, Yan-Wen Lv
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  ABSTRACT: A novel series of quinolone derivatives (6a-6n) were designed and synthesized, and their biological activities were evaluated as potential antitumor Top I inhibitors. Among these compounds, 6j exhibited the most potent antitumor activities against multiple cancer cell lines. Docking simulation was performed to insert compound 6j into the crystal structure of DNA-Top I to determine the probable binding model.
  Chemical & pharmaceutical bulletin 04/2013;
• Article: Synthesis of some novel thieno[3,2-d]pyrimidines as potential cytotoxic small molecules against breast cancer.

  Manal Kandeel, Mohammed Kamal Abdelhameid, Madlen Berty Labib
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  ABSTRACT: A variety of novel thieno[3,2-d]pyrimidines with different decorating functional groups were synthesized as a part of a study aiming to enrich the arsenal of chemotherapeutic agents for the treatment of cancer. The design of synthetic molecules based on DNA-interchelating properties by hydrogen bond formation. The reported compounds herein are: 4-aminothienopyrimidine derivatives 4a,b and their 4-substituted phenylamino analogues 8a,b; 4-thienopyrimidin-4-ones 5a,b; N-alkyl thienopyrimidin-4-ones 6a-g; 4-chlorothienopyrimidines 7a,b; and thienopyrimidoquinazolinones 9a,b which are the structural mimics of 8a,b. The synthesized molecules were evaluated for their in vitro cytotoxic activity against human breast cancer cell line (MCF-7). Biological screening revealed varying cytotoxic potencies of the tested molecules compared with Doxorubicin as a reference drug. The cytotoxicity results from the study suggested that the synthesized molecules are potential antitumor agents and compound 4a was the most potent with an IC 50 2.04 nM.
  Chemical & pharmaceutical bulletin 03/2013;
• Article: Measurement of Transport Activities of 3β-Hydroxy-Δ5-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS.

  Tsuyoshi Murai, Kana Oda, Terutake Toyo, Hiroshi Nittono, Hajime Takei, Akina Muto, Akihiko Kimura, Takao Kurosawa
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  ABSTRACT: A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ5-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ5-bile acids using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ5-bile acids. The present study demonstrated that human multidrug resistance-associated protein 3 vesicles accepted conjugated 3β-hydroxy-Δ5-bile acids along with common bile acids such as glycocholic acid and taurolithocholic acid 3-sulfate.
  Chemical & pharmaceutical bulletin 03/2013;
• Article: Prediction of compatibility between ozagrel sodium preparation for injection and calcium on the basis of the solubility product.

  Mio Tange, Miyako Yoshida, Mai Hazekawa, Tamami Haraguchi, Yuka Nakai, Takahiro Uchida
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  ABSTRACT: The purpose of the study was to evaluate the compatibility of ozagrel sodium solution and calcium-containing transfusions using solubility product constants. We calculated the solubility product constant of mixtures of ozagrel sodium and calcium chloride and evaluated the compatibility of ozagrel sodium solution (both the original and generic products) with calcium chloride solution using a light obscuration particle counter. Various volumes of ozagrel solution were added to the calcium solutions to make final ozagrel concentrations of 0, 0.8, 1.6, 2.0, 2.4, 3.2 and 4.0 mmol/L. The solutions were gently agitated and stored at 25 and 40°C. The ozagrel concentration, calcium ion concentration and number of microparticles were measured. The solubility product constants obtained were 11.89×10-9 mol3/L3 (at 25°C) and 7.82×10-9 mol3/L3 (40°C). The number of insoluble microparticles was significantly increased when the ionic product was larger than the solubility product constant. In all ozagrel sodium products, the number of insoluble microparticles was within the allowable range according to the Japanese Pharmacopoeia. These results suggest that mixing ozagrel sodium with calcium-containing products is safe and without appreciable risk of incompatibility under clinical conditions.
  Chemical & pharmaceutical bulletin 03/2013;
• Article: Effects of Phosphate Buffer in Parenteral Drugs on Particle Formation from Glass Vials.

  Toru Ogawa, Makoto Miyajima, Naoki Wakiyama, Katsuhide Terada
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  ABSTRACT: The characteristics of inorganic particles generated in glass vials filled with phosphate buffer solutions were investigated. During storage, particles were visually detected in the phosphate buffer solution in particular glass vials which pass compendial tests of containers for injectable drugs. These particles were considered to be different from ordinal glass delamination, which has been reported in a number of papers because the particles were mainly composed of Al, P and O, but not Si. The formation of the particles accelerated at higher storage temperatures. Among the surface treatments tested for the glass vials, sulfur treatment showed a protective effect on the particle formation in the vials, whereas the SiO(2) coating did not have any protective effects. It was found that the elution ratio of Al and Si in the solution stored in the glass vials after the heating was similar to the ratio of Al and Si in borosilicate glass. However, the Al concentration decreased during storage (5°C, 6 months), and consequently, particle formation was observed in the solution. Adding citrate, which is a chelating agent for Al, effectively suppressed the particle formation in the sterilized solution. When 50 ppb and higher concentrations of Al ion were added to the phosphate buffer solution, the formation of white particles containing Al, P and O was detected. It is suggested that a phosphate buffer solution in a borosilicate glass vial has the ability to form particles due to interactions with the Al that is eluted from the glass during storage.
  Chemical & pharmaceutical bulletin 02/2013;
• Article: Nocapyrones H-J, 3,6-disubstituted a-pyrones from the Marine Actinomycete Nocardiopsis sp. KMF-001.

  Min Cheol Kim, Oh-Wook Kwon, Jin-Soo Park, Sunyeou Kim, Hak Cheol Kwon
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  ABSTRACT: Three new 3,6-disubstituted a-pyrones, nocapyrones H-J (1-3), were isolated from the marine actinomycete Nocardiopsis sp. KMF-001. Their structures were assigned to be 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones on the basis of UV, MS, NMR, and HRFABMS analyses. Nocapyrone H (1) reduced the pro-inflammatory factor such as nitric oxide (NO), prostaglandin E(2)(PGE(2)) and interleukin-1β (IL-1β). Moreover, nocapyrone H showed 5.82% stronger inhibitory effect on NO production than chrysin at a concentration of 10 μM in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells.
  Chemical & pharmaceutical bulletin 02/2013;
• Article: Preparation and Evaluation of Sustained-Release Doxazosin Mesylate Pellets.

  Jung-Myung Ha, Ju-Young Kim, Tack-Oon Oh, Yun-Seok Rhee, Sang-Cheol Chi, Hyun Kuk, Chun-Woong Park, Eun-Seok Park
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  ABSTRACT: Doxazosin mesylate (DXM) sustained release pellets were prepared by an extrusion-spheronization and fluid-bed coating technique. The core pellets containing DXM were prepared by extrusion-spheronization technique, and coated by a fluid-bed coater to control the release of DXM. The factors affecting to properties of pellets, such as diluent content, type and coating level of coating agents and plasticizers were studied in the present study. Polymethacrylate derivatives (Eudragit(®) RS PO and RL PO) were used for coating agents, and PEG 6000, TEC and castor oil were as plasticizers. To evaluate the properties of prepared pellets, the size of prepared pellets was investigated by sieve analysis technique and the morphology of pellets was evaluated by scanning electron microscopy. Through the dissolution test, factors that have an effect on the dissolution of the drug were evaluated. As the content ratio of MCC had increased, the dissolution was proportionally sustained. Eudragit(®) RS PO had more marked sustaining effect on the dissolution rate than Eudragit(®) RL PO, and the effect was more pronounced with the increased coating level. PEG 6000 was an appropriate plasticizer for DXM pellets, and increasing the content of PEG 6000, was also slightly decreasing the dissolution rate.
  Chemical & pharmaceutical bulletin 02/2013;
• Article: Synthesis of a Novel Polymeric Material Folate-Poly (2-ethyl-2-oxazoline)-Distearoyl Phosphatidyl Ethanolamine Tri-block Polymer for Dual Receptor and pH-sensitive Targeting Liposome.

  Guimin Xia, Zhijiao An, Yang Wang, Chen Zhao, Mei Li, Zichen Li, Jie Ma
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  ABSTRACT: The in vivo distribution of antitumor drugs is usually lack of selectivity, and thus, leading to a low efficacy of chemotherapy on cancers and high toxicity to normal cells. Receptor-mediated targeting liposome with pH-sensitivity as a dual drug delivery system is one of the efficient approaches to overcome the disadvantages. The study was to synthesize a novel smart polymeric material (folate-poly (2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine, F-PEOz-DSPE), which can combine with the folate-receptor (FR) over-expressed on cancer cells and respond to pH changes in endosome-lysosome system in cancer cells to rapidly release drug simultaneously.The F-PEOz-DSPE was synthesized by the method of asymmetric synthesis of organic polymer and characterized by IR, (1)H NMR, ESI-MS and GPC. To investigate the properties of targeting and pH-sensitivity of F-PEOz-DSPE, Blank liposomes, blank fluorescently labeled liposomes and doxorubicin (DOX)-loaded liposomes containing F-PEOz-DSPE or PEOz-DSPE or DSPE were prepared. The cytotoxicity, cellular uptake and drug cumulative release in vitro were investigated. Blank liposomes modified with PEOz block had little cytotoxicity in vitro. The liposomes containing F-PEOz-DSPE showed a higher affinity to human ovarian cancer cell SKOV3, a FR(+) cancer cells, than those with PEOz-DSPE. A higher drug cumulative release from DOX-loaded liposomes containing F-PEOz-DSPE or PEOz-DSPE in vitro was found in phosphate buffered saline at pH 5.0 medium than at pH 7.4. These results indicate that F-PEOz-DSPE exhibits selective targeting, pH-sensitivity and little cytotoxicity, and may be a promising polymeric material for dual receptor and pH-sensitive targeting liposome.
  Chemical & pharmaceutical bulletin 02/2013;
• Article: Fluorophotometric Determination of Histone with 3,4,5,6-Tetrafluoro-2-carboxyphenylfluorone--Manganese(II) Complex and Its Characterization.

  Kanako Miyachi, Mitsuru Hoshino, Hiroko Kadobayashi, Kenzo Moriyama, Mamiko Asano, Takako Yamaguchi, Yoshikazu Fujita
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  ABSTRACT: A simple fluorophotometric method for the determination of histone has been developed. This method involves a fluorescence quenching reaction that results in the formation of a complex of manganese(II), 3,4,5,6-tetrafluoro-2-carboxyphenylfluorone (TFCPF), and histone in a non-ionic surfactant micellar medium. The calibration curve was found to be linear in the range of 0.5 to 2.0μg/mL. The binding parameters (n, number of binding sites; K, binding constant) and thermodynamic parameters (ΔG(0), change in Gibbs free energy; ΔH(0), change in enthalpy; ΔS(0), change in entropy) were investigated spectrophotometrically for the elucidation of the reaction mechanism. The resulting binding parameters (n=4.08 and K=3.16×10(4)M(-1) at 25°C) and thermodynamic parameters (ΔG=-25.83kJ/mol,ΔH=-9.83kJ/mol,, and ΔS=53.68J/(molK)) suggest that the colored complex in this reaction system is an ion-association complex between manganese(II)--TFCPF and histone.
  Chemical & pharmaceutical bulletin 02/2013;
• Article: Eight New Diterpenoids and Two New Nor-Diterpenoids from the Stems of Croton cascarilloides.

  Susumu Kawakami, Hiroki Toyoda, Liva Harinantenaina, Katsuyoshi Matsunami, Hideaki Otsuka, Takakazu Shinzato, Yoshio Takeda, Masatoshi Kawahata, Kentaro Yamaguchi
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  ABSTRACT: From the stems of Croton cascarilloides, eight new diterpenoids, named crotocascarins A-H (1-8), having a crotofolane skeleton were isolated along with two new nor-diterpenoids (9 and 10), named crotocascarins α and β, derived through rearrangement of the crotofolane skeleton. The structures of these compounds were elucidated by means of extensive one- and two-dimensional NMR spectroscopic analyses. The absolute structures of the diterpene moiety were determined by application of the CD rule for the γ-lactone ring. The relative structures of the two crotofolanes (1 and 2) and one rearranged compound (9) were confirmed by X-ray crystallographic analyses. Compounds 1, 2 and 9 possessed 2-methylbutyric acid in their molecules, the absolute configuration of which was found to be 2S by comparison of its HPLC behavior with that of an authentic sample. Therefore, the absolute structures of these crotocascarins (1, 2 and 9) were unambiguously determined. The absolute structures of crotofolanes are reported for the first time in this paper.
  Chemical & pharmaceutical bulletin 02/2013;
• Article: Synthesis and biological evaluation of xanthine derivatives on dipeptidyl peptidase 4.

  Kuaile Lin, Zhengyan Cai, Fei Wang, Wei Zhang, Weicheng Zhou
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  ABSTRACT: A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the results of SAR study of the series, the compounds with 4-methyl-quinazoline-2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities. Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8.
  Chemical & pharmaceutical bulletin 01/2013;
• Article: Inhibition of P-glycoprotein mediated multidrug resistance by stemofoline derivatives.

  Sonthaya Umsumarng, Komsak Pintha, Pornsiri Pitchakarn, Kwankamol Sastraruji, Thanapat Sastraruji, Alison Ung, Araya Jatisatienr, Stephen Pyne, Pornngarm Limtrakul
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  ABSTRACT: Resistance to chemotherapy in cancer patients has been correlated to the overexpression of the ATP-binding cassette (ABC) drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. We examined the mutidrug resistance reversing property of stemofoline derivatives in drug-resistance human cervical carcinoma (KB-V1) and human leukemic (K562/Adr) cell lines that overexpress P-gp. Didehydrostemofoline and eleven of its derivatives were synthesized and the cytotoxicity and their effect on doxorubicin, vinblastine and paclitaxel sensitivity in drug resistant (KB-V1 and K562/Adr) and drug sensitive (KB-3-1 and K562) cell lines by an MTT assay were determined. We found that three out of the twelve stemofoline derivatives including OH-A1, NH-B6 and NH-D6 showed commitment efficiency to increase sensitivity to doxorubicin, vinblastine and paclitaxel in KB-V1 cells and increase sensitivity to doxorubicin, and paclitaxel in K562/Adr cells whereas the effects have not been seen in their parental sensitive cancer cell lines (KB-3-1 and K562). These results indicate that stemofoline derivatives reversed P-gp-mediated multidrug resistance in vitro, and thus could be developed as effective chemosensitizers to treat multidrug-resistant cancers. The molecular mechanism of modulation of P-gp would be further determined.
  Chemical & pharmaceutical bulletin 01/2013;
• Article: Triterpenoid saponins of Pulsatilla koreana root have inhibition effects of TNF-α secretion in LPS-induced RAW 264.7 cells.

  Wei Li, Yan Ding, Ya Nan Sun, Xi Tao Yan, Seo Young Yang, Chun Whan Choi, Ji Yun Cha, Young Mi Lee, Young Ho Kim
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  ABSTRACT: In the present study, a new oleanane-type triterpenoid saponin, pulsatilloside F (1), along with 21 known compounds (2-22), were isolated from the root of Pulsatilla koreana. Their chemical structures were elucidated by mass, (1)H, (13)C NMR, COSY, HMQC and HMBC spectroscopy. Anti-inflammatory effects of the compounds were evaluated in terms of inhibitory of tumor necrosis factor α (TNF-α) secretion in the lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophage cell line. Compounds 19 and 20 exhibited particularly inhibitory effects with respective IC(50) values of 0.32 and 0.65 μM. Compounds 1-4, 7 and 10-13 exhibited inhibitory effects with inhibition rates up to 41.55-73.76% at a concentration of 5 μM, respectively.
  Chemical & pharmaceutical bulletin 01/2013;
• Article: Himeic Acids E-G, New 4-Pyridone Derivatives from a Culture of Aspergillus sp.

  Toshiyuki Kuwana, Mitsue Miyazaki, Hikaru Kato, Sachiko Tsukamoto
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  ABSTRACT: Three new himeic acids E-G were isolated from a marine-derived fungus, Aspergillus sp., and their structures were determined by spectroscopic analysis. Although himeic acid A inhibited the activity of ubiquitin-activating enzyme (E1), the three new derivatives did not.
  Chemical & pharmaceutical bulletin 01/2013; 61(1):105-7.
• Article: Induced Production of Methyl Bromodihydroxyphenyl Acetates by the Marine-Derived Fungus Aspergillus sp.

  Alain Simplice Leutou, Keumja Yun, Jung Sook Kang, Byeng Wha Son
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  ABSTRACT: The addition of metal bromides (NaBr and CaBr2) during fermentation of a marine isolate of the fungus Aspergillus sp. induced production of two new brominated dihydroxyphenylacetic acid derivatives, methyl 2-(6-bromo-3,4-dihydroxyphenyl)acetate (1) and methyl 2-(2,5-dibromo-3,4-dihydroxyphenyl)acetate (2), and a known compound, 2-(3,4-dihydroxyphenyl)acetic acid (3). The structures of the two new compounds (1, 2) were assigned through the combination of spectroscopic data analyses and comparison with the spectral data of compound 3. Compounds 1-3 exhibited potent radical-scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) with IC50 values (14.2, 12.1, 11.0 µm, respectively) demonstrating greater activity than the positive control (l-ascorbic acid; IC50, 20.0 µm).
  Chemical & pharmaceutical bulletin 01/2013; 61(4):483-5.