Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Volume 62, Issue 7
Displaying 1-16 of 16 articles from this issue
Regular Articles
  • Toshihide Abe, Yoshitsugu Yanagihara, Tomonobu Uchino, Toyohito Oriyam ...
    2014 Volume 62 Issue 7 Pages 617-626
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    The formulation characteristics of 6 brands of enteric-coated aspirin tablets under unpackaged conditions at 40°C and 60°C for 4 weeks were analyzed. Appearance, salicylic acid content, dissolution rates, and surface properties (by Raman microscopy) were evaluated to determine stability data, taking into account the clinical use of generic drugs. No change in appearance, decomposition, or dissolution rates was observed in unpackaged aspirin tablets stored at 40°C for 4 weeks. However, when stored at 60°C, tablets of 5 of the 6 brands showed whiskers on their surfaces along with an increase in salicylic acid content and a decrease in dissolution rate. Results of Raman mapping on the surface and cross sectional surface of the tablets with whiskers showed a salicylic acid peak associated with storage at 60°C for 4 weeks. However, for tablets from 1 of the 6 brands, no salicylic acid peaks were observed. For this tablet, Raman microscopy revealed 2 layers of film coating, and talc, which greatly affected the stability of the acetylsalicylic acid, was found only in the outer layer film. These results indicated that the protection of compatibility with talc is one of the important factors in enhancement of aspirin tablet stability in this tablet. We concluded that certification of the characteristics associated with stability and formulation is essential for generic drugs, which are not required to undergo stability testing under extreme storage conditions.
  • Doudou Xu, Lijun Wang, Dana Gourevich, Eihab Kabha, Fabian Arditti, Mu ...
    2014 Volume 62 Issue 7 Pages 627-635
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Supplementary material
    A novel γ-cyclodextrin (γ-CD) based carrier for molecular encapsulation of cancer chemotherapeutic agent doxorubicin (DOX) was synthesized and fully characterized by various analytical approaches. The γ-CD derivative, with a β-naphthyl alanine residue attached in its primary face, exhibits potent binding capacity with DOX. The encapsulation efficiency was assessed under various temperatures and pHs and it was demonstrated that the carrier-DOX inclusion complex is highly stable under a wide range of acidic conditions (pH 1.0–7.0); however, the encapsulated drug is slowly released under hyperthermic conditions (up to 50°C). Cell culture studies showed that the complexation of DOX with the carrier protected the drug from being uptaken by the cells and also greatly reduced its toxicity. Thermo-triggered DOX release was validated and the increase in cellular uptake was observed in in-vitro experiments. We concluded that this novel γ-CD derivative is able to effectively encapsulate DOX and the inclusion is responsive to temperature change, hence renders it a potential encapsulating agent for DOX delivery in combination with hyperthermia treatments.
  • Keiichi Motoyama, Yuki Tanida, Kyona Hata, Tomoya Hayashi, Taishi Higa ...
    2014 Volume 62 Issue 7 Pages 636-641
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
    Advance online publication: April 16, 2014
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    A megamolecular polysaccharide sacran was newly extracted from cyanobacterium Aphanothece sacrum. Sacran has many preferable properties for transdermal application, e.g. a safe biomaterial, a high moisturizing effect, a formation of film and hydrogel. Additionally, it was recently discovered that sacran has an anti-inflammatory effect for atopic dermatitis model mice. In this study, in order to evaluate the feasibility of sacran-hydrogel as a novel sustained release system, we prepared a sacran-hydrogel containing 4-biphenyl acetic acid (BPAA, an acidic drug), prednisolone (PD, a neutral drug) or chlorpheniramine maleate (CPM, a basic drug), and performed the in vitro release studies. The sacran-hydrogel containing BPAA, PD or CPM provided a sustained release profile in accordance with a quasi-Fickian diffusion model. Furthermore, the release rate of drugs from sacran-hydrogels can be controlled by adjusting the concentration of aluminum chloride as a cross linker. These results suggest the potential use of sacran-hydrogel as a sustained release system for drugs.
  • Shinya Ariyasu, Yuki Mizuseda, Kengo Hanaya, Shin Aoki
    2014 Volume 62 Issue 7 Pages 642-648
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    8-Hydroxyquinoline (HQ)-based compounds have recently been proposed as potential candidates for drugs for treating human immunodeficiency virus (HIV), cancer, neurodegenerative diseases (Alzheimer’s and Parkinson’s disease), and parasitic and bacterial infections. However, HQ itself and its derivatives might be toxic due to their intrinsic affinity for metal cations in living systems. One possible strategy for suppressing the toxicity and side effects of drugs with metal chelation properties, such as HQ, would be masking the critically important moieties with protecting groups that can be subsequently removed under specific conditions. In our previous work, we reported that HQ analogs are potent and selective inhibitors (Ki values=0.16–29 µM) of aminopeptidase from Aeromonas proteolytica (AAP) (EC 3.4.11.10), a dinuclear Zn2+ peptidase. Based on this background information, HQ sulfonates were synthesized as prodrugs of HQ-based AAP-inhibitors that can be reactivated by photochemical cleavage of the S–O bond in the sulfonate groups. The findings indicate that HQ sulfonates containing methanesulfonyl and 2-aminoethanesulfonyl groups are essentially stable under physiological conditions and undergo photolysis to regenerate the corresponding HQ compounds that function as AAP inhibitors. This methodology could be applied to the design of similar types of Zn2+ hydrolase inhibitors and prodrugs.
  • Takaki Amamoto, Tomofumi Santa, Masaru Kato
    2014 Volume 62 Issue 7 Pages 649-653
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Supplementary material
    We have developed a general method for controlling molecular functions using a photodegradable hydrogel; gels containing molecules made from such materials are capable of release and activation by light stimulus. As the elimination of molecular leaching from the gel before irradiation was a barrier to the precise control of molecular function, we optimized the monomer used in gel preparation during this study. The addition of N,N′-methylenebis(acrylamide) (MBAA) inhibited molecular leaching from the gel; the MBAA concentration is a critical factor in controlling the leaching of encapsulated molecules. We succeeded in preparing a gel that halved the leaching of small encapsulated molecules, while the leaching of large molecules, such as albumin (66 kDa) and ferritin (450 kDa), was at negligible levels, or disappeared. The on/off ratios (released amount/leached amount) of albumin and ferritin were 8 and 17, respectively.
  • Shogo Hiraoka, Shinya Uchida, Noriyuki Namiki
    2014 Volume 62 Issue 7 Pages 654-660
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    The aim of this study was to obtain injectable high-drug-loading core–shell structure microspheres that release aripiprazole over 2 months. The microparticles were prepared by the oil-in-water emulsion solvent evaporation method and characterized. The microparticles were prepared with aripiprazole and 3 types of poly(lactic acid) (PLA) (DL-PLA: molecular weight (MW), ca. 20000; DL-PLA: MW, ca. 95000; or L-PLA: MW, ca. 110000), which were dissolved within the organic phase, and prepared in 3 temperature conditions for the external aqueous phase (two fixed temperature conditions and a gradually increased temperature condition). The theoretical drug loading in the particles was set to 80%. When prepared at fixed temperature conditions, all of the microparticles that were prepared with the 3 types of PLA were not spherical or smooth-surfaced. These microparticles released 100% of the drug within 1 week in the in vitro study. However, the microparticles that were prepared with DL-PLA (MW, 95000) in the gradually increased temperature condition were spherical with a smooth surface. The dissolution profile of the microparticles showed a long release over 7 weeks in vitro. The actual drug loading in the microspheres was 73–80%. A core–shell structure was observed in the inner structure of the microspheres. The core–shell microspheres were injected subcutaneously into rabbits. Aripiprazole was detected in the serum over 12 weeks. Production of high-drug-loading core–shell structure microspheres was successfully achieved by using high molecular weight of PLA and specific temperature condition at preparation. It showed long release profile in vitro and in vivo.
  • Takefumi Yamashita, Akihiko Ueda, Takashi Mitsui, Atsushi Tomonaga, Sh ...
    2014 Volume 62 Issue 7 Pages 661-667
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Supplementary material
    The computational structure-based drug design (SBDD) mainly aims at generating or discovering new chemical compounds with sufficiently large binding free energy. In any de novo drug design methods and virtual screening methods, drug candidates are selected by approximately evaluating the binding free energy (or the binding affinity). This approximate binding free energy, usually called “empirical score,” is critical to the success of the SBDD. The purpose of this work is to yield physical insight into the approximate evaluation method in comparison with an exact molecular dynamics (MD) simulation-based method (named MP-CAFEE), which can predict binding free energies accurately. We calculate the binding free energies for 58 selected drug candidates with MP-CAFEE. Here, the compounds are generated by OPMF, a novel fragment-based de novo drug design method, and the ligand–protein interaction energy is used as an empirical score. The results show that the correlation between the binding free energy and the interaction energy is not strong enough to clearly distinguish compounds with nM-affinity from those with µM-affinity. This implies that it is necessary to take into account the natural protein motion with explicitly surrounded by water molecules to improve the efficiency of the drug candidate selection procedure.
  • Chung-Kyu Ryu, Ji-Hee Nho, Guohua Jin, Sun Young Oh, Soo Jung Choi
    2014 Volume 62 Issue 7 Pages 668-674
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
    Advance online publication: May 01, 2014
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    Benzofuro[6,7-d]thiazoles, benzofuro[7,6-d]thiazoles and 6-arylaminobenzo[d]thiazole-4,7-diones were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species and Cryptococcus neoformans. Among them tested, many of synthesized compounds showed potent antifungal activity. The compounds 4d, 6e and 6h completely inhibited the growth of all Candida and Aspergillus species tested at the MIC level of 6.3 µg/mL. The results suggest that benzofuro[6,7-d]thiazoles and 6-arylaminobenzo[d]thiazole-4,7-diones would be promising antifungal agents.
  • Ismail Mahmoud Elfekki, Walid Fathalla Mohamed Hassan, Hosam Eldin Abd ...
    2014 Volume 62 Issue 7 Pages 675-694
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Cobalamin-dependant cytosolic enzyme methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine (Hcy) to produce methionine and tetrahydrofolate (THF). MetS is over-expressed in the cytosol of certain breast and prostate tumour cells. Methionine used as a source of one carbon atom for the building of the DNA of the tumour cells, structural protein and enzymes. In this study, we designed, synthesized and evaluated the cytotoxic activity of a series of substituted methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)acetate and dipeptide that mimic the substructure of MTHF. These inhibitors were docked in to the MTHF binding domain in such the same way as MTHF in its binding domain. The free energies of the binding were calculated and compared to the IC50 values. This series has been developed by dicyclohexylcarbodiimide (DCC) and azide coupling methods of amino acid esters with carboxylic acid derivatives, respectively. Compound methyl 3-hydroxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetamido)propanoate exhibited the highest IC50 value 20 µg/mL against PC-3 cell line and scored the lowest free energy of the binding (−207.19 kJ/mol).
  • Bo Huang, Hui-Zheng Fu, Wei-Kang Chen, Yue-Hua Luo, Shuang-Cheng Ma
    2014 Volume 62 Issue 7 Pages 695-699
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
    Advance online publication: May 08, 2014
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    Supplementary material
    Four new triterpenoid saponins, 2α,3α,19α,24-tetrahydroxyolean-12-en-28-oic-acid 28-O-β-D-glucopyranosyl ester (1), 2α,3α,19α,23-tetrahydroxyolean-12-en-28-oic-acid 28-O-β-D-xylopyranosyl-(1→2)-β-D-glu-copyranosyl ester (2), 2α,3α,19α-trihydroxyolean-12-en-28-oic-acid 28-O-β-D-xylopyranosyl-(1→2)-β-D-glucopyranosyl ester (3), 2α,3α,23,29-tetrahydroxyurs-12,19-dien-28-oic-acid 28-O-β-D-glucopyranosyl ester (4), together with three known compounds (57), were isolated from the leaves of Callicarpa nudiflora HOOK. Their structures were established by means of spectroscopic methods and chemical evidence. Hepatoprotective activities of the isolated compounds against D-galactosamine-induced toxicity have been tested. Among them, compounds 13 showed pronounced hepatoprotective activities against D-galactosamine-induced toxicity in WB-F344 rat hepatic epithelial stem-like cells.
  • Shinya Fujii, Takanobu Kobayashi, Aki Nakatsu, Hiroshi Miyazawa, Hiroy ...
    2014 Volume 62 Issue 7 Pages 700-708
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Nuclear transcription factor nuclear factor-kappa B (NF-κB) has diverse pathophysiological functions, and NF-κB inhibitors are considered to be candidates for multiple therapeutic applications. We previously reported a novel triazine-based NF-κB inhibitor, 2-anilino-4,6-dichloro-1,3,5-triazine (NI241), that directly inhibits DNA binding of NF-κB. Here, we report synthesis of a series of triazine derivatives and evaluation of their structure–activity relationships for NF-κB inhibition. We found that 2-amino-4,6-dichloro-1,3,5-triazine substructure is essential for the inhibitory activity of the lead compound NI241, and modification of NI241 by introduction of an m-methoxy substituent on the phenyl ring afforded the more potent derivative 28. The structure–activity relationships identified in this study suggested a possible mechanism of irreversible NF-κB inhibition by NI241, and should be helpful in the design of other NF-κB inhibitors.
Notes
  • Mituhiro Kuriyama, Kaichiro Haruta, Takenori Dairaku, Takuya Kawamura, ...
    2014 Volume 62 Issue 7 Pages 709-712
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Supplementary material
    Mercury pollution poses a severe threat to human health. To remove Hg2+ from contaminated water, we synthesized Hg2+-trapping beads that include oligo-thymidine functionalities that can form thymine–Hg(II)–thymine base pairs on the solid support. The beads can selectively trap Hg2+ even in the presence of other metal cations. More interestingly, Hg2+-trapping efficiency was higher in the presence of the co-existing cations. Thus, the developed Hg2+-trapping beads can capture Hg2+ without affecting the mineral balance of water so much. The Hg2+-trapping beads presented here show promise for removing Hg2+ from environmental water.
  • Sung Ryul Lee, Jong Hwan Kwak, Su Jin Noh, Julius Ryan Pronto, Kyung S ...
    2014 Volume 62 Issue 7 Pages 713-718
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
    Advance online publication: April 24, 2014
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    Supplementary material
    Sodium nitroprusside (SNP) releases nitric oxide (NO), a powerful vasodilator, and thus widely used in intensive care unit for treating hypertension emergency. However, cardiac toxicity after SNP administration is a clinical problem. For finding a natural compound that suppressing SNP-induced cardiac toxicity, we tested the protective potential of kobophenol A (Kob A), purified from the root of Caragana sinica, against the toxic effects of SNP. The severe cardiac H9c2 cell death was induced by SNP (2 mM) treatment. Kob A ameliorated SNP-induced cardiac H9c2 cell death, and this protective effect of Kob A may be related to the inhibition of c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase activation following SNP administration. In addition, the downregulation of cellular Bcl-2 and Mcl-1 levels by SNP exposure was strongly abrogated in the presence of Kob A. These biological properties of Kob A might provide insights into developing new cardioprotectant against SNP-induced cardiac cell death.
  • Ying Tang, Yong-bo Xue, Lei Zhou, Jin-wen Zhang, Guang-min Yao, Zeng-w ...
    2014 Volume 62 Issue 7 Pages 719-724
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
    Advance online publication: April 15, 2014
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    Supplementary material
    Phytochemical investigations of the tubers of Dioscorea bulbifera L. resulted in the isolation of nine norclerodane diterpenoids, including two new compounds, diosbulbins N (1) and P (3), a new naturally occurring compound, diosbulbin O (2), and six known ones, diosbulbins A–D, F and G (4–9). Their structures were established by spectroscopic and chemical methods. The absolute stereochemistry of 1 was determined by a modified Mosher’s method, and the absolute configuration of 2 was determined by a single-crystal X-ray diffraction analysis with CuKα irradiation. Compounds 1–3 were evaluated for in vitro cytotoxicity against five human cancer cell lines.
  • Masanori Kuroyanagi, Osamu Shirota, Setsuko Sekita
    2014 Volume 62 Issue 7 Pages 725-728
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Transannular cyclizations of germacrone-4,5-epoxide under acidic and thermal conditions have been reported in our previous study. However, this process gave the different and interesting results under basic conditions. (4S,5S)-Germacrone-4,5-epoxide (1) was treated under basic conditions to yield four products (25). Compound 2 was an isomer of 1 —(4S,5S,9Z)-4,5-epoxygermacra-7(11),9-dien-8-one— and the remaining three compounds (35) were eudesmane-type derivatives. Compounds 4 and 5 are new compounds. The structures of the new compounds were determined using high resolution (HR)-MS, one dimensional (1D)-NMR, 2D-NMR and circular dichroism (CD) spectroscopic data. Products 35 had the same carbon skeleton as that of eudesmane-type compounds; however, these compounds showed different arrangement of isoprene units to the natural eudesmane-type sesquiterpenes.
  • Lin Wu, Xiaobing Wang, Siming Shan, Jun Luo, Lingyi Kong
    2014 Volume 62 Issue 7 Pages 729-733
    Published: July 01, 2014
    Released on J-STAGE: July 01, 2014
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    Supplementary material
    Six new cassane diterpenoids, named caesalls H–M (16), were isolated from the seed kernels of Caesalpinia bonduc. Their structures were elucidated on the basis of spectroscopic analysis, mainly NMR and MS. The absolute configurations of compounds 1 and 3 were determined by a single-crystal X-ray study using a mirror Cu radiation and circular dichroism (CD) spectra, respectively. None of the compounds were cytotoxic against HepG-2, MCF-7 and MG-63 cells.
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