Chemical and Pharmaceutical Bulletin
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ISSN-L : 0009-2363
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Volume 56, Issue 5
Displaying 1-26 of 26 articles from this issue
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Regular Articles
  • Application and Mechanism of Inhalation Profile Improvement of DPI Formulations by Mechanofusion with Magnesium Stearate
    Michiko Kumon, Satoshi Machida, Masahiko Suzuki, Akira Kusai, Etsuo Yo ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 617-625
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.617
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    In our previous paper, we reported the inhalation properties of dry powder inhaler (DPI) formulations containing Compound A and mechanofusion-processed lactose carriers. The mechanofusion process with magnesium stearate (Mg-St) on the lactose carrier enhanced the fine particle fraction (FPF) value of the Andersen cascade impactor (ACI) study. The increase of FPF seemed to be associated with the increase of the dispersibility of drug particles. The objectives of this study were (1) to evaluate the applicability of lactose carrier mechanofusion-processed with Mg-St and (2) to examine the mechanism of FPF alteration by the mechanofusion process applied on the lactose carrier with or without additive. The inhalation profiles of DPI formulations containing four different pharmaceutical compounds were evaluated with an ACI. The dispersibility of the formulations was observed by particle size distribution measurement in the air stream and the adhesive force was measured bydirect separation method. It was found that higher FPF was obtained with lactose mechanofusion-processed with Mg-St as compared to control lactose carriers for all four compounds. This suggested that mechanofusion process with Mg-St is widely applicable in DPI formulations. The homogenization of surface adhesiveness was attributed to the increased FPF of the DPI including lactose mechanofusion-processed with Mg-St, as suggested by the combination of several physicochemical characteristics. Combination of different characterization methods would be of help to clarify the whole mechanism which defines the inhalation properties of DPI formulations.
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  • Synthesis and Biological Evaluation of Amide Derivatives of (6-Chloro-2,3-dihydro-1H-inden-1-yl)acetic Acid as Potential Anti-inflammatory Agents with Lower Gastrointestinal Toxicity
    Meenakshi Sharma, Saumendra Mohan Ray
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 626-634
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.626
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    A variety of amide derivatives of (6-chloro-2,3-dihydro-1H-inden-1-yl)acetic acid were synthesized and screened for their anti-inflammatory and related biological activities. These compounds were found to be longer acting and showed residual activity exceeding that of standard indomethacin. The studies with SKF-525A, a standard hepatic microsomal enzyme inhibitor showed that probably the test compound per se is the active species. The compound 6y showed best activity profile with ED30 of 6.45 mg/kg however this compound was found to be toxic at 100 mg/kg p.o. Though these compounds exhibited appreciable analgesic and antipyretic activities but they failed to prevent the development of secondary inflammation in adjuvant induced arthritis assay. The compound 6x showed 94% inhibition of acetic acid induced writhing. Studies showed that antagonism of TNF-α is not possibly involved in the mechanism of action of these compounds. However these compounds were found to have only mild ulcerogenic potential at the tested dose level of 100 mg/kg p.o. in comparison to indomethacin.
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  • Dynamic Interaction among the Platform Domain and Two Membrane-Proximal Immunoglobulin-Like Domains of Class I Major Histocompatibility Complex: Normal Mode Analysis
    Hiroyuki Nojima, Mayuko Takeda-Shitaka, Kazuhiko Kanou, Kenshu Kamiya, ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 635-641
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.635
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    Class I major histocompatibility complex (MHC) molecules have three domains, a platform domain and two membrane-proximal immunoglobulin-like domains, an α3 domain and a β2-immunoglobulin (β2m). To understand the dynamic interactions among the three domains, we simulated the behavior of a partial model deficient in β2m and another model deficient in the α3 domain, by normal mode analysis. As a result, the partial model deficient in β2m was more flexible in interdomain conformation than the other model. The lowest frequency modes (<2 cm−1) observed for the simulations of the partial model deficient in β2m showed clear interdomain motions as if each domain moved like a rigid body. Such low frequencies and clear interdomain motions were not observed for the simulations of the other model, therefore the interdomain flexibility of the partial model deficient in β2m may be due to the lowest frequency modes (<2 cm−1). These results suggest that β2m contributes to maintaining the interdomain conformation of class I MHC molecules more than the α3 domain does, and may offer convincing evidence to support the notion that the α3 domain and β2m do not have an equal influence on the structural stability of class I MHC molecules.
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  • New Lanostane Triterpene Lactones from the Vietnamese Mushroom Ganoderma colossum (FR.) C. F. BAKER
    Riham Salah El Dine, Ali Mahmoud El Halawany, Norio Nakamura, Chao-Mei ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 642-646
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.642
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    Four new lanostane triterpene lactones (colossolactone I, colossolactone II, colossolactone III and colossolactone IV) were isolated from the Vietnamese mushroom Ganoderma colossum (FR.) C. F. BAKER along with five known compounds. The structures of the new compounds were determined on the basis of MS, NMR and circular dichroism.
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  • Michael Adducts—Source for Biologically Potent Heterocycles
    Adivireddy Padmaja, Gali Sudhakar Reddy, Annaji Venkata Nagendra Mohan ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 647-653
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.647
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    A new class of pyrimidinetriones, thioxopyrimidinediones, pyrazolidinediones and isoxazolidinediones were prepared from (E)-1,4-diarylbut-2-ene-1,4-diones. All the new compounds synthesized were screened for antimicrobial activity.
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  • Synthesis of Novel Purinyl-1′-homocarbanucleosides Based on a Cyclopenta[b]pyrazine System
    Carmen Balo, Carmen López, Olga Caamaño, Franco Fern&aac ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 654-658
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.654
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    cis-2,3-Diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazine-5,7-dimethanol, prepared by Diels–Alder reaction from cyclopentadiene and appropriately protected 2-imidazolone—followed by dihydroxylation, glycol protection, diamine deprotection, condensation with benzyl, glycol deprotection, oxidative cleavage and reduction—, was used to synthesize (±)-cis-{[7-(6-chloro-9H-purin-9-yl)methyl]-2,3-diphenyl-6,7-dihydro-5H-cyclopenta[b]pyrazin-5-yl}methanol, a key intermediate for novel 1′-homocarbanucleosides based on a cyclopenta[b]pyrazine scaffold as shown by its conversion into several 6-substituted purinyl derivatives.
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  • Preparation, Characterization and in Vitro Anticancer Activity of Platinum(II) Complexes with N-Cyclohexyl-1,3-propanediamine as the Carrier
    Weiping Liu, Chen Qing, Xizhu Chen, Qingsong Ye, Yao Yu, Shuqian Hou
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 659-662
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.659
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    New JM118 (active form of satraplatin) analogues with N-cyclohexyl-1,3-propanediamine (N-chpda) as the carrier, cis-[Pt(N-chpda)X2] (X2=2Cl− (1), oxalate (2), malonate (3), 1,1-cyclobutanedicarboxylate (CBDCA) (3), and 3-hydroxy-1,1-cyclobutanedicarboxylate(HO-CBDCA) (4)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray crystal structure for a representative compound cis-[Pt(N-chpda)Cl2].The complexes have also been evaluated for their in vitro anticancer activity. All these analytical data are in good agreement with the structures of the desired compounds. The Pt(II) is in a square planar environment and is coordinated by a chelating N-chpda ligand and 2Cl− in cis position, and there are two crystallographically independent cis-[Pt(N-chpda)Cl2] molecules linked together by intermolecular N–H···Cl hydrogen bonds. Compounds 1 and 2 are very active against human lung cancer cell line (AGZY) and human lymphocytic leukemia cell line (Raji), and are much more active than carboplatin. Platinum(II) complexes with N-cyclohexyl-1,3-propanediamine is an alternative choice for mixed ammine/aminoplatinum anticancer drugs.
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  • Partitioning of Anti-inflammatory Steroid Drugs into Phosphatidylcholine and Phosphatidylcholine-Cholesterol Small Unilamellar Vesicles as Studied by Second-Derivative Spectrophotometry
    Shigehiko Takegami, Keisuke Kitamura, Takako Funakoshi, Tatsuya Kitade
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 663-667
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.663
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    The partition coefficients (Kps) of six anti-inflammatory steroid drugs, dexamethasone (DMS), betamethasone (BMS), triamcinolone acetonide (TCLA), fluocinolone acetonide (FCLA), betamethasone 17,21-dipropionate (BMSDP), and clobetasole propionate (CBSP), for phosphatidylcholine (PC), and PC-cholesterol small unilamellar vesicles (SUVs) were determined by a second-derivative spectrophotometric method. The Kp values were obtained with a relative standard deviation of below 10% and the following order was observed: BMS≤DMS<TCLA<FCLA<<BMSDP<CBSP. BMSDP which has a structure that the two hydroxyl groups of BMS are esterified with propionic acid showed a largely enhanced Kp value of 10.5 times that of BMS. Further, replacement of a propionate group in BMSDP with a chlorine atom resulted in the highest Kp value (CBSP) within the drugs examined, i.e., the Kp value of CBSP was 1.2 times that of BMSDP. The presence of 30 mol% cholesterol in the SUV bilayers reduced these Kp values to approximately 35—50% of those values for the PC SUVs, although the order of the Kp values remained unchanged. The order of the Kp values agreed with that of the reported dermatological therapeutic potency of these drugs, although the order of their log P values for n-octanol/water systems showed a discrepancy. Our results indicate that the potency of steroid drugs in dermatological treatments depends to some extent on the Kp values of the drug, that is, the affinity of steroid drugs for PC bilayers influences their clinical potency, since potency is related to transdermal absorption.
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  • Formation and Characterization of Emulsions Using β-Cyclodextrin as an Emulsifier
    Motoki Inoue, Kaname Hashizaki, Hiroyuki Taguchi, Yoshihiro Saito
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 668-671
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.668
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    The preparation and characterization of n-alkane/water emulsions using β-cyclodextrin (β-CD) were studied. The prepared n-alkane/water emulsions were of the oil-in-water (O/W) type, and the stability of emulsions was in the order of n-hexadecane > n-dodecane > n-octane. From observations using polarized light microscopy and powder X-ray diffraction measurement, it was suggested that the formation of a dense film at the oil–water interface and the three-dimensional structural network created by precipitated complexes in the continuous phase are associated with the stability of emulsion. Furthermore, it was clarified that O/W-type emulsions were formed because the contact angle (θow) which the precipitate makes with the interface was θow < 90° in all compounds (oils) used in this study.
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  • Coordination of Divalent Metal Cation to Amide Group to Form Adduct Ion in FAB Mass Spectrometry: Implication of Zn2+ in Enzymatic Hydrolysis of Amide Bond
    Hisayoshi Kobayashi, Naoko Morisaki, Hiroyuki Miyachi, Yuichi Hashimot ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 672-676
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.672
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    The structures of complexes between amides and metal ions were examined by FAB mass spectrometry and collision-induced dissociation (CID). Zn2+ was coordinated by the amide carbonyl oxygen atom of N-tetradecylacetamide (1). In contrast, Ca2+ and Mg2+ were coordinated by the amide group of 1 in both the keto and enol forms. The catalytic role of Zn2+ at the active site of the hydrolases might partly be explained by the effective attack of Zn2+ on carbonyl oxygen atom of the scissile amide group.
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  • Sesquiterpenoids Isolated from Eupatorium glehnii. Isolation of Guaiaglehnin A, Structure Revision of Hiyodorilactone B, and Genetic Comparison
    Motoo Tori, Norie Morishita, Naoko Hirota, Yoshinori Saito, Katsuyuki ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 677-681
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.677
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    A new sesquiterpenoid substituted with unsaturated ester, guaiaglehnin A (1), along with 15 previously known compounds, were isolated from the methanol extract of the terrestrial part of Eupatorium glehnii (Compositae) collected in Nagano Prefecture, Japan, the results of which supported the previous study by Takahashi et al. The chemical constituents of E. glehnii collected in Nagano Prefecture and those collected in Tokushima or Hokkaido are quite different, depending on collection site, although the species are identical. The base sequences of three different samples were identical. Diversity in the chemical components was detected, though no diversity existed in the DNA sequence. In this study, eupasimplicin A (2) was also isolated, whose presence in the extract of E. chinense simplicifolium was recorded but not in an article. The side chain geometry of hiyodorilactone B (5) was revised to be E.
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  • Structure Activity Relationships of Quinoxalin-2-one Derivatives as Platelet-Derived Growth Factor-β Receptor (PDGFβ R) Inhibitors, Derived from Molecular Modeling
    Yoshikazu Mori, Takatsugu Hirokawa, Katsuyuki Aoki, Hisanori Satomi, S ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 682-687
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.682
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    We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-β receptor (PDGFβ R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFβ R-ligand interactions, is urgently needed. Here we present models of the PDGFβ R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by α-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFβ R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors.
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  • Trypsin-Catalyzed Synthesis of Dipeptide Containing α-Aminoisobutylic Acid Using p- and m-(Amidinomethyl)phenyl Esters as Acyl Donor
    Haruo Sekizaki, Kunihiko Itoh, Akiyoshi Shibuya, Eiko Toyota, Mareshig ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 688-691
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.688
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    Two series of inverse substrates, p- and m-(amidinomethyl)phenyl esters derived from N-(tert-butyloxycarbonyl)amino acid, were prepared as acyl donor components for enzymatic peptide synthesis. They were found to be readily coupled with an acyl acceptor such as L-alanine p-nitroanilide to produce dipeptide. An α-aminoisobutyric acid containing dipeptide was especially obtained in satisfactory yield. Streptomyces griseus trypsin was a more efficient catalyst than the bovine trypsin. The optimum condition for the coupling reaction was studied by changing the organic solvent, pH, and acyl acceptor concentration. It was found that the enzymatic hydrolysis of the resulting product was negligible.
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  • Light Irradiation Is a Factor in the Bactericidal Activity of Silver-Loaded Zeolite
    Yoshihiro Inoue, Makoto Kogure, Ken-ichiro Matsumoto, Hajime Hamashima ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 692-694
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.692
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    Silver loaded zeolite (Ag-Z) was previously found to have effective bactericidal activity against Escherichia coli. To understand the mechanisms of bactericidal activity of Ag-Z, role of light irradiation was focused and investigated in this study. In this study, we focused on light irradiation. Antibacterial assay and spectroscopic study revealed that light irradiation enabled Ag-Z to reduce dioxygen to form a reactive oxygen species, which led to bactericidal activity. These results indicate that the onset of bactericidal activity can be controlled by light irradiation.
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  • Reinvestigation of Absolute Stereostructure of (−)-Rosiridol: Structures of Monoterpene Glycosides, Rosiridin, Rosiridosides A, B, and C, from Rhodiola sachalinensis
    Masayuki Yoshikawa, Seikou Nakamura, Xuezheng Li, Hisashi Matsuda
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 695-700
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.695
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    Three new (−)-rosiridol glycosides, rosiridosides A, B, and C, were isolated from the roots of Rhodiola sachalinensis together with rosiridin [(−)-rosiridol 1-O-β-D-glucopyranoside]. In the course of the structure elucidation of those new glycosides, the absolute configuration of the 4-position in (−)-rosiridol was reinvestigated. On the basis of the application of the modified Mosher's method for (−)- and (+)-rosiridol derivatives, the absolute configuration of the 4-position in (−)-rosiridol should be revised to be S orientation from the recently assigned R form, so that the absolute stereostructures of rosiridosides A, B, and C and rosiridin were determined.
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  • Pseudorotaxane-Like Supramolecular Complex of Coenzyme Q10 with γ-Cyclodextrin Formed by Solubility Method
    Katsunori Nishimura, Taishi Higashi, Ayumi Yoshimatsu, Fumitoshi Hiray ...
    Article type: Regular Article
    2008 Volume 56 Issue 5 Pages 701-706
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.701
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    The purpose of this study is to reveal whether Coenzyme Q10 (CoQ10) forms pseudorotaxane-like supramolecular complex with γ-cyclodextrin (γ-CyD). The poorly soluble complex of CoQ10 with γ-CyD in water was prepared by the solubility method. The X-ray diffraction pattern of the CoQ10/γ-CyD complex was different from that of the physical mixture, but almost the same as that of polypropylene glycol (PPG)/γ-CyD polypseudorotaxane. Also, the differential scanning calorimetrical study and FT-IR study demonstrated the interaction between CoQ10 and γ-CyD in the solid state. The 1H-NMR study and the yield study of the supramolecular complex of CoQ10 with γ-CyD demonstrated that the stoichiometry was 5 : 1 (γ-CyD : CoQ10). The dispersion rate of CoQ10 was markedly increased by the formation of the supramolecular complex with γ-CyD, possibly due to submicron-ordered particle formulation. In fact, CoQ10 was found to form submicron-sized supramolecular particles with γ-CyD, when prepared by the solubility method. Consequently, the present study showed that CoQ10 forms the pseudorotaxane-like supramolecular complex with γ-CyD in water.
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Notes
Communicatins to the Editor
  • Bioinformatics Based Ligand-Docking and in-Silico Screening
    Daisuke Takaya, Mayuko Takeda-Shitaka, Genki Terashi, Kazuhiko Kanou, ...
    Article type: Communications to the Editor
    2008 Volume 56 Issue 5 Pages 742-744
    Published: May 01, 2008
    Released on J-STAGE: May 01, 2008
    DOIhttps://doi.org/10.1248/cpb.56.742
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    We report a novel method, ChooseLD (CHOOse biological information Semi-Empirically on the Ligand Docking), which uses simulated annealing (SA) based on bioinformatics for protein–ligand flexible docking. The fingerprint alignment score (FPAScore) value is used to determine the docking conformation of the ligand. This method includes the matching of chemical descriptors such as fingerprints (FPs) and the root mean square deviation (rmsd) calculation of the coordinates of atoms of the chemical descriptors. Here, the FPAScore optimization for the translation and rotation of a rigid body is performed using the Metropolis Monte Carlo method. Our ChooseLD method will find wide application in the field of biochemistry and medicine to improve the search for new drugs targeting various proteins implicated in diseases.
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