Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 58, Issue 8
Displaying 1-25 of 25 articles from this issue
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Regular Articles
  • Synthesis, Characterization, Cytotoxic Activities, and DNA-Binding Studies of Ternary Copper(II) Complexes with New Coumarin Derivatives
    Lei Jia, Xi-Ming Xu, Jun Xu, Long-Hai Chen, Peng Jiang, Fei-Xiang Chen ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1003-1008
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1003
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    In this study, two novel complexes [Cu(MCVH)phen(H2O)]·ClO4 (1) and [Cu(MCLH)phen(H2O)]·ClO4 (2) (here, MCVH2=(7-hydroxy-4-methyl-8-coumarinyl) valine, MCLH2=(7-hydroxy-4-methyl-8-coumarinyl) leucine) have been synthesized and characterized by elemental analyses, molar conductance, infrared spectra (IR), 1H-NMR and UV–Vis measurements. The interactions of them with calf thymus DNA (ct DNA) have been investigated by absorption spectroscopy, fluorescence spectroscopy, circular dichroism spectroscopy and viscosity measurements. Experimental results reveal an intercalative interaction with DNA for the complexes, furthermore the binding affinity of 2 is higher than that of 1 according to the calculated binding constant values. In addition, they were evaluated for their cytotoxic activities toward human prostate cancer cell (PC3), human liver cell (L02) and human myeloid leukemia cancer cell (HL-60) by acid phosphoatase assay. Both of them showed significant cytotoxic potency.
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  • A New Method for Evaluating the Bitterness of Medicines in Development Using a Taste Sensor and a Disintegration Testing Apparatus
    Tsutomu Harada, Takahiro Uchida, Miyako Yoshida, Yoshikazu Kobayashi, ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1009-1014
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1009
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    The purpose of this study was to demonstrate the usefulness and wide applicability of a taste sensor and a new disintegration testing apparatus in the development and/or evaluation of orally disintegrating tablets (ODTs). In this paper, we described methods for the effective utilization of a taste sensor in the development of a new medicine. First we predicted the taste of propiverine hydrochloride, a model drug substance whose taste is unknown, using a taste sensor. Then we screened masking agents for their ability to suppress the bitterness of propiverine hydrochloride, and manufactured ODTs of propiverine hydrochloride with various masking agents. The tastes of these ODTs were then evaluated in chronological order by combining the taste sensor with the new disintegration testing apparatus, ODT-101, to resemble the oral cavity. As a result, we were able to evaluate the taste of propiverine hydrochloride and the effectiveness of various masking agents in ODTs. The result using this combination of taste sensor and ODT-101 shows good agreement with the results of human gustatory sensation testing, thus demonstrating the usefulness and applicability of the taste sensor and disintegration testing apparatus, ODT-101, in the development of new medicine.
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  • Preparation and the in Vitro Evaluation of Nanoemulsion System for the Transdermal Delivery of Granisetron Hydrochloride
    Wen-wu Zheng, Ling Zhao, Yu-meng Wei, Yun Ye, Shun-han Xiao
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1015-1019
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1015
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    The objective of this study was to develop and evaluate nanoemulsion system for transdermal delivery of granisetron hydrochloride. Pseudo-ternary phase diagram was constructed to ascertain the concentration range of components of nanoemulsion composed of isopropyl myristate (IPM) as an oil phase, tween 85 as surfactant, ethanol as cosurfactant, water as aqueous phase. The effects of the content of IPM as an oil phase and n-methyl pyrrolidone (NMP) as transdermal enhancer on rat skin permeation of granisetron hydrochloride nanoemulsion were studied in vitro. The results showed that the mean particle size of nanoemulsion ranged from 50.4±1.5 to 82.4±0.9 nm with homogeneous size distribution. The resulted optimum formulation composed of 2.5% granisetron hydrochloride, 4% IPM, 40% tween 85/ethanol (1 : 1) and 10% NMP showed that the skin permeation rate was the highest (85.39±2.90 μg/cm2/h) and enhancement of drug permeability was 4.1-folde for transdermal delivery of granisetron hydrochloridein comparison with the control group (20% of tween 85 and 20% of ethanol micelle solution containing 2.5% of granisetron hydrochloride without IPM), and cumulative permeation amount was the highest (891.8±2.86 μg/cm2) with the shortest lag time (0.11±0.02 h) and was stable for at least 12 months. Therefore, the nanoemulsion system developed in this study offers a promising vehicle for the transdermal delivery system of granisetron hydrochloride, which may be as effective as oral or intravenous dosage forms and avoid some difficulties associated with these dosage forms.
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  • 1-(3′-[125I]Iodophenyl)-3-methy-2-pyrazolin-5-one: Preparation, Solution Stability, and Biodistribution in Normal Mice
    Yuuhei Sano, Tomokazu Motomura, Fumihiko Yamamoto, Miki Fukuda, Takahi ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1020-1025
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1020
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    3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1), known as a potent free radical scavenger, has been developed as a medical drug for the treatment of acute cerebral infarction. With the aim of developing radiotracers for imaging free radicals in vivo, 1-(3′-[125I]iodophenyl)-3-methy-2-pyrazolin-5-one (125I-2) was synthesized by two methods, via isotopic exchange and interhalogen exchange under solvent-free conditions, in which iodo- and bromo-derivatives were used as labeling precursors, respectively. After HPLC purification, 125I-2 was obtained in modest isolated radiochemical yields (ca. 20%) with high radiochemical purities by both methods. The former gave specific activities of 0.2—0.6 kBq/μmol, whereas the latter approach achieved specific activities of more than 0.14 GBq/μmol. On attempting to prepare an injectable formulation for 125I-2 with high specific activity, its radiochemical purities dropped to about 60—70%. Unlabeled analog 2 was found to have lipophilic and antioxidant properties similar to edaravone. Intravenous injection of 125I-2 with low specific radioactivity into normal mice showed signs of distribution profiles similar to reported results for 14C-labeled edaravone in normal rats.
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  • Crotalionosides A—C, Three New Megastigmane Glucosides, Two New Pterocarpan Glucosides and a Chalcone C-Glucoside from the Whole Plants of Crotalaria zanzibarica
    Junko Shitamoto, Katsuyoshi Matsunami, Hideaki Otsuka, Takakazu Shinza ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1026-1032
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1026
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    From a 1-BuOH-soluble fraction of the MeOH extract of the leaves of Crotalaria zanzibarica collected in the Okinawa Islands, three new megastigmane glucosides, named crotalionosides A—C, two new pterocarpan glucosides and a chalcone C-glucoside were isolated together with two known flavonoid glycosides and one known megastigmane glucoside. The structures of the new compounds were elucidated by a combination of spectroscopic analyses. The absolute configurations of allenic megastigmane glucosides were determined by application of the modified Mosher's method. Those of the allenic moieties were determined by interpretation of the circular dichroism (CD) spectra of the reduction products derived from citrosides A and B. The aglycones of pterocarpan glucosides were found to be melilotocarpan B and the absolute structure of the chalcone C-glucoside was determined by comparison of the CD spectral behavior with the reported values.
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  • Azaphilone and Isocoumarin Derivatives from the Endophytic Fungus Penicillium sclerotiorum PSU-A13
    Jiraporn Arunpanichlert, Vatcharin Rukachaisirikul, Yaowapa Sukpondma, ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1033-1036
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1033
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    Two new azaphilone derivatives, penicilazaphilones A (1) and B (2), and one new isocoumarin, penicilisorin (3), together with six known compounds were isolated from the endophytic fungus Penicillium sclerotiorum PSU-A13. Their structures were identified by analysis of spectroscopic data. The antimicrobial activity against Staphylococcus aureus, Candida albicans and Cryptococcus neoformans as well as the inhibitory effect on human immunodeficiency virus (HIV)-1 integrase and protease were examined.
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  • Development and in Vitro Evaluation of Ibuprofen Mouth Dissolving Tablets Using Solid Dispersion Technique
    Sunil Kumar Jain, Meenakshi Shukla, Vivek Shrivastava
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1037-1042
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1037
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    The aim of present study was to prepare and evaluate mouth dissolving tablets of ibuprofen (IBU). Ternary solid dispersion (SD) of IBU was prepared using PEG 4000 as carrier and Tween 80 as surfactant. The SD formulations were prepared by solvent evaporation and melt solvent method by varying ratio of PEG 4000. Different weight ratio of carrier, drug and surfactant 5 : 5 : 1, 10 : 5 : 1, 25 : 5 : 1, 35 : 5 : 1 and 45 : 5 : 1 was taken. The prepared SD formulations were characterized by Fourier Transform Infra-Red (FT-IR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and in vitro drug release. Mouth dissolving tablets of IBU were formulated using optimized SD formulation of carrier : drug : surfactant ratio, 10 : 5 : 1 along with super-disintegrants. The best developed formulation was compared with marketed tablet product of IBU. From IR and XRD studies, it may be concluded that there is change in crystalline form of drug into amorphous during formation of SD. From DSC studies, it was predicted that drug was completely dissolved in the carrier. Mouth dissolving tablets containing Ac-Di-Sol (12%) as super-disintegrant showed the fastest disintegration (202s) and in vitro drug release (84.57%). The release pattern of all developed formulations followed Peppas–Korsmeyer model as the plot between log cumulative % drug released versus log time showed good linearity (r>0.99) with a comparatively high slope (n) value within the range of 0.44—0.67. The tablets containing SD exhibited better dissolution profile than commercial tablets.
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  • Dolabellane Diterpene and Three Cycloartane Glycosides from Thalictrum squarrosum
    Hitoshi Yoshimitsu, Hiroyuki Miyashita, Makiko Nishida, Tomoko Mineno, ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1043-1046
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1043
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    A new dolabellane diterpene glycoside, named squoside A, and three new cycloartane glycosides, named squarrosides V, VI, and VII, have been isolated from the dried aerial parts of Thalictrum squarrosum (Ranunculaceae). Their structures were determined by two dimensional (2D) NMR spectroscopic analysis and chemical evidence.
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  • In Vitro Leishmanicidal Activity of Benzophenanthridine Alkaloids from Bocconia pearcei and Related Compounds
    Hiroyuki Fuchino, Marii Kawano, Kanami Mori-Yasumoto, Setsuko Sekita, ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1047-1050
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1047
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    Leishmanicidal activities of benzophenanthridine alkaloids isolated from fruits of Bocconia pearcei and their derivatives were examined. Seven benzophenanthridine compounds were isolated from the methanolic extracts of B. pearcei. Among them, dihydrosanguinarine showed the most potent leishmanicidal activities (IC50 value: 0.014 μg/ml, respectively). To examine the structure–activity relationship of the benzophenanthridine skeleton, the leishmanicidal activities for 32 synthetic samples were examined. The existence of bulky groups at the C7–C8 position was found to enhance the activity. On the other hand, the bulkiness at the C2–C3 position on the D-ring, a carbonyl group at C-6, substitution at C-6 and cleavage or saturation of the C5–C6 bond reduced activity. A methyl group on nitrogen of the C-ring was thought to be necessary for significant activity.
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  • Evaluation of Serum Protein Binding by Using in Vitro Pharmacological Activity for the Effective Pharmacokinetics Profiling in Drug Discovery
    Yukinori Kawai, Yoshimine Fujii, Katsuya Akimoto, Masayuki Takahashi
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1051-1056
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1051
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    The establishment of a new index for the profile of serum protein binding was analyzed theoretically. The in vitro pharmacological activity ratio of the inhibition constant in the absence of serum protein to that in its presence (activity ratio), which represents the extent of specific binding to serum protein, was suggested as the new index. To clarify the usefulness of the activity ratio, theoretical analysis by the activity ratio for 3% human serum albumin was examined in comparison with conventional methods of equilibrium dialysis. In-house very late antigen-4 antagonists were used as model compounds, whose pharmacokinetics were strongly influenced by serum protein binding. Although the theoretical and actual unbound fractions were similar, the latter tended to be slightly lower than the former. This small difference was considered to correspond to nonspecific binding. These results suggested that the specific and nonspecific binding could be discriminated by comparing the activity ratio data with those of conventional methods. Moreover, the activity ratio was suggested to be useful in profiling the influence of protein binding on pharmacokinetics. In conclusion, it was considered that the activity ratio could avoid the risk of misleading interpretation by nonspecific binding in pharmacokinetics/pharmacological activity. Moreover, the activity ratio was considered to be valuable as one of the useful parameters in pharmacokinetics profiling and as a tool of rational drug design for drug discovery.
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  • Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: Indoline-Based Sulfamide Derivatives with Low Lipophilicity and Protein Binding Ratio
    Kenji Takahashi, Masaru Ohta, Yoshimichi Shoji, Masayasu Kasai, Kazuyo ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1057-1065
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1057
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    To find a novel acyl-CoA: cholesterol acyltransferase inhibitor, a series of sulfamide derivatives were synthesized and evaluated. Compound 1d, in which carboxymethyl moiety at the 5-position of Pactimibe was replaced by a sulfamoylamino group, showed 150-fold more potent anti-foam cell formation activity (IC50: 0.02 μM), 1.6-fold higher log D7.0 (4.63), and a slightly lower protein binding ratio (93.2%) than Pactimibe. Compound 1i, in which the octyl chain at the 1-position in 1d was replaced by an ethoxyethyl, showed markedly low log D7.0 (1.73) and maintained 3-fold higher anti-foam cell formation activity (IC50: 1.0 μM), than Pactimibe. The plasma protein binding ratio (PBR) of 1i was much lower than that of Pactimibe (62.5% vs. 98.1%), and its partition ratio to the rabbit atherosclerotic aorta after oral administration was higher than that of Pactimibe. Compound 1i at 10 μM markedly inhibited cholesterol esterification in atherosclerotic rabbit aortas even when incubated with serum, while Pactimibe had little effect probably due to its high PBR. In conclusion, compound 1i is expected to more efficiently inhibit the progression of atherosclerosis than Pactimibe.
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  • Novel Tetrahydroisoquinoline Derivatives with Inhibitory Activities against Acyl-CoA: Cholesterol Acyltransferase and Lipid Peroxidation
    Masaru Ohta, Kenji Takahashi, Masayasu Kasai, Yoshimichi Shoji, Kazuyo ...
    Article type: Regular Article
    2010 Volume 58 Issue 8 Pages 1066-1076
    Published: August 01, 2010
    Released on J-STAGE: August 01, 2010
    DOIhttps://doi.org/10.1248/cpb.58.1066
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    To find a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor with anti-lipid peroxidative activity, a series of tetrahydroisoquinoline derivatives were synthesized and evaluated. A compound with a N-(4-hydroxy-2,3,5-trimethylphenyl)carbamoyl moiety at the 3-position and an octanoyl moiety at the 2-position (7) was demonstrated to show anti-foam cell formation activity stronger than and anti-lipid peroxidative activity comparable to those of Pactimibe, while it was hardly absorbed orally. To increase its bioavailability, the acyl chain at the 2-position was shortened and various polar or basic moieties were introduced at the 7-position of 7. Among the synthesized derivatives, (S)-7-dimethylamino-N-(4-hydroxy-2,3,5-trimethylphenyl)-2-isobutyryl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide hydrochloride (21) showed about 16-fold stronger anti-foam cell formation activity, 3-fold stronger hepatic ACAT inhibitory activity, similar anti-low density lipoprotein (LDL) oxidative activity and 2-fold more potent protective activity against macrophage cell death by oxidative stress in comparison with Pactimibe. Compound 21 was efficiently absorbed after oral administration at 10 mg/kg in rats and dogs and its Cmax values were higher than its IC50 values for in vitro activities. In conclusion, a tetrahydroisoquinoline structure is a useful scaffold for designing a phenolic anti-oxidative ACAT inhibitor, and compound 21 is expected to effectively prevent atherosclerosis.
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