Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 55, Issue 7
Displaying 1-30 of 30 articles from this issue
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Review
  • Synthetic Organic Chemistry Based on Small Ring Compounds
    Hideo Nemoto
    2007 Volume 55 Issue 7 Pages 961-974
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.961
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    Small ring systems are important topics in both organic and inorganic chemistry, and draw considerable attention from both theoretical and preparative perspectives. This review intends to summarize the studies, focusing on the preparative aspects, that have been carried out in our laboratory. Namely, synthesis of (+)- and (−)-α-cuparenone, (+)-ipomeamarone, (+)-epiipomeamarone, (−)-ngaione, (−)-α-bisabolol, (−)-aplysin, (−)-debromoaplysin, (−)-mesembrine, (−)-filiformin, (−)-debromofiliformin, and (−)-4-deoxyverrucarol via successive asymmetric epoxidation and enantiospecific ring expansion of cyclopropylidenes, (+)-equilenin via successive ring expansion–insertion reaction, estrone, estradiol, chenodeoxycholic acid, 19-norspironolactone, 19-nordeoxycorticosterone, cortisone, adrenosterone, 11-oxoprogesterone, and 1α,25-dihydroxyvitamin D3 via intramolecular cycloaddition reaction of o-quinodimethanes. Medicinal chemistry aiming at developing a new type of anti-influenza agent, novel reaction mode of electrocyclic reaction, and substituent effect on that reaction are also discussed.
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Regular Articles
  • Characterization of Dual Layered Pellets for Sustained Release of Poorly Water-Soluble Drug
    Tae-Wan Kim, Hongkee Sah, Beom-Jin Lee
    2007 Volume 55 Issue 7 Pages 975-979
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.975
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    The aim of this study was to develop pellet formulations that could be used to improve the dissolution and bioavailability of a poorly water-soluble model drug, cisapride. Six different types of pellets were prepared by coating sugar spheres in a fluidized bed coater. When the sugar spheres were single layered containing cisapride and solubilizer such as polysorbate 80, the resulting pellets provided an instant release of cisapride in the simulated gastric fluid. Dissolution tests carried out in the simulated intestinal fluid showed that there were negligible amounts of cisapride released, regardless of the pellet formulation. To succeed in attaining dissolution and the sustained release of cisapride at a neural pH, the single layered pellets were coated again with a coating suspension containing Eudragit® RS 30D and L 30D. Scanning electron microscopy revealed that the dual layered pellets had a crack-free and spherical surface. Interestingly, the dual layered pellets provided the sustained release of cisapride in both the simulated gastric and intestinal fluids. The composition and components of the dual layers were found to be key parameters affecting the pattern of cisapride dissolution. Significant improvement in the bioavailability of cisapride was achieved when the dual layered pellets were administered orally to dogs. Overall, these results suggest that the dual layered pellets have potential as a sustained release dosage form for poorly water-soluble drugs.
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  • A Simple Method to Improve the Odds in Finding ‘Lead-Like’ Compounds from Chemical Libraries
    Kouhei Horio, Hajime Muta, Junichi Goto, Noriaki Hirayama
    2007 Volume 55 Issue 7 Pages 980-984
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.980
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    A simple method of virtual screening is proposed. This method uses only chemical characters calculated from two dimensional chemical structures. Local and global chemical characters are represented by molecular fingerprint and trait, respectively. The trait is a newly introduced concept in this paper and it is expressed by a set of two dimensional (2D) molecular descriptors. In this study, both the molecular fingerprint and the trait were used to represent drug-likeness of a group of molecules with a particular pharmacological activity. To learn about the molecular fingerprint and trait specific to a particular group of drugs, we used a database of drugs that are clinically used in Japan now. The molecular fingerprint and trait trained on these real drugs were used to predict drug-likeness of molecules in other chemical databases. In these chemical databases, an appreciable number of compounds that show the relevant pharmacological activity are contained. Some of these compounds are drugs clinically used abroad, but not in Japan. The prediction rate was judged by an enrichment factor. Despite the simplicity of the methodology, practical results were obtained. In the case of β-adrenergic blockers, the enrichment factor of 66 was attained and nearly 57% of active molecules in the chemical databases were successfully covered.
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  • Submicron Particles of SBA-15 Modified with MgO as Carriers for Controlled Drug Delivery
    Shoucang Shen, Pui Shan Chow, Fengxi Chen, Reginald Beng Hee Tan
    2007 Volume 55 Issue 7 Pages 985-991
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.985
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    Submicron particles with modified surface were synthesized by a simple one-pot synthesis approach and used as drug carrier for controlled release. Due to the alkalinity of MgO species on the surface, the amount of a model drug, ibuprofen, adsorbed on the modified surface was increased as compared to pure silica SBA-15 although the surface area was decreased by the surface modification. FTIR investigation indicated that the adsorption state of ibuprofen on MgO modified SBA-15 was different from that on pure silica SBA-15 and pure crystal ibuprofen. The result obtained from in vitro release test exhibited that the surface modification greatly decreased the ibuprofen release rate. In first 6 h in vitro release test, only 63% of the adsorbed ibuprofen was released from the MgO/SBA-15 (Si/Mg=20). In contrast, the release of ibuprofen was complete in 1 h from the pure silica SBA-15 under the same release conditions. The surface modified with MgO created affinity with acidic ibuprofen molecules and retarded the release rate from the mesoporous matrix. In addition, the release rate of ibuprofen could be modulated by varying the content of MgO, and was found to decrease with increasing amount of MgO on surface of SBA-15 submicron particles.
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  • An Unambiguous Assignment and Structural Analysis Using Solution NMR Experiments of O-Antigen from Escherichia coli ATCC23505 (Serotype O9)
    Rui Tada, Noriko Nagi-Miura, Yoshiyuki Adachi, Naohito Ohno
    2007 Volume 55 Issue 7 Pages 992-995
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.992
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    Bacterial lipopolysaccharide from Escherichia coli O9 (O9 LPS) has various characteristic biological activities other than endotoxic activities. The biological activities exhibited depend on the structure of the O-antigen. The O-antigen region of O9 LPS is composed of the mannose homopolysaccharide (MHP). This structure was reported previously, but not all its proton and carbon signals were assigned. In the present study, we completely assign all proton and carbon signals of the O-antigen of O9 LPS using 1H- and 13C-NMR spectroscopy, including the DQF-COSY, TOCSY, NOESY, HSQC, H2BC, HSQC-TOCSY and HMBC methods.
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  • Two New Co(II) and Ni(II) Complexes with 3-(2-Pyridyl)pyrazole-Based Ligand: Synthesis, Crystal Structures, and Bioactivities
    Chun-Sen Liu, Hang Zhang, Ran Chen, Xue-Song Shi, Xian-He Bu, Ming Yan ...
    2007 Volume 55 Issue 7 Pages 996-1001
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.996
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    Two new Co(II) and Ni(II) complexes exhibiting DNA cytotoxic activities with 3-(2-pyridyl)pyrazole-based ligand, [Co(L)3](ClO4)2 (1) and [Ni(L)3](ClO4)2 (2) (L=1-[3-(2-pyridyl)-pyrazol-1-ylmethyl]-naphthalene) were synthesized and structurally characterized. Both 1 and 2 crystallized in the monoclinic system, space group P2(1)/c, for 1, a=12.8324(8), b=12.1205(8), c=33.27(2) Å, β=93.92(3)° and Z=4; for 2, a=12.8764(3), b=12.1015(3), c=33.2415(9) Å, β=93.998(1)° and Z=4. Among them, the Co(II) and Ni(II) ions were all coordinated by six N donors from three distinct L ligands. In addition, the cytotoxic activities of 1, 2 and L in vitro were evaluated against three different cancer cell lines HL-60 (human leukemia), BGC-823 (stomach cancer) and MDA-MB-435 (mammary cancer), respectively. The results showed that 1 exhibited significantly high cytotoxic activities against HL-60 and moderate activities against BGC-823 and MDA-MB-435. In order to further investigate the relationships between structures and DNA-binding behaviors of these complexes, the interactions of 1, 2 and L with calf thymus DNA (CT-DNA) were then subjected to thermal denaturation, viscosity measurements and spectrophotometric methods. The results indicated that 1 and 2 intercalated with DNA via L ligand. The intrinsic binding constants of 1, 2 and L with DNA were 1.6×104, 5.6×103 and 2.76×103 M−1, respectively.
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  • Development of a Stick-Type Transdermal Eyelid Delivery System of Ketotifen Fumarate for Ophthalmic Diseases
    Chiharu Kimura, Kakuji Tojo
    2007 Volume 55 Issue 7 Pages 1002-1005
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1002
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    A transdermal eyelid delivery system for treating ocular diseases (eye-stick) has been developed. Ketotifen fumarate (KT) was used as a model drug. An in vivo study using rabbits showed that the eye-stick device maintained a constant conjunctival concentration of the drug for an extended period of time, which was equivalent or higher than the therapeutic level following eye drop administration. Moreover, the conjunctival concentration after eye-stick application was well predicted using the physicochemical parameters, diffusion coefficient and partition coefficient, obtained from in vitro hairless mouse skin permeation experiments.
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  • On the Interaction of Doxorubicin with Oleate Ions: Fluorescence Spectroscopy and Liquid–Liquid Extraction Study
    Emilie Munnier, Frédéric Tewes, Simone Cohen-Jonathan, C ...
    2007 Volume 55 Issue 7 Pages 1006-1010
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1006
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    Increase of lipophilicity of cationic doxorubicin (DOX) by its association with a fatty acid ion is of interest for pharmaceutical formulations and could have an impact on the drug delivery into cancer cells. On the basis of spectroscopic analysis of intrinsic DOX fluorescence, this study provides an experimental evidence of DOX–oleate interactions as function of ion/drug molar ratio (R) and pH. An electrostatic attraction to oleates is dominant for the cationic form of DOX (pH 6.5) and a hydrophobic interaction is characteristic of the molecular form of DOX (pH 8.6). A high content of sodium oleate vesicles ([oleate]≥0.2 mM, R≥20) limits the electrostatic and hydrophobic interactions at pH 6.5 while favoring the hydrophobic interactions at pH 8.6. The influence of these interactions on the lipophilicity of the cationic form of DOX is analyzed by measuring the apparent partition coefficient (aqueous buffer pH 6.5/methylene chloride). The results show a lipophilicity gain for the cationic form of DOX in presence of 10 : 1 ion/drug molar ratio, while no lipophilicity increase is observed at 50 : 1 molar ratio.
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  • Novel Polymer-Supported Chiral Catalysts for the Asymmetric Addition of Diethylzinc to Aldehydes
    Su-Xi Wang, Fen-Er Chen
    2007 Volume 55 Issue 7 Pages 1011-1013
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1011
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    Newly synthesized polymer-supported chiral amino alcohol catalysts 5a and 5b have been proved to be effective for the enantioselective addition of diethylzinc to aldehydes, affording the corresponding sec-alcohols in moderate enantiomeric excesses with good to excellent yields. The recycled catalyst could be reused in the same reaction without significant deterioration in performance.
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  • Synthesis and Antibacterial Activity of Bis[2-amino-4-phenyl-5-thiazolyl] Disulfides
    Hamid Latif Siddiqui, Muhammad Zia-ur-Rehman, Naveed Ahmad, George Wil ...
    2007 Volume 55 Issue 7 Pages 1014-1017
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1014
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    Different dimeric disulfides, having the basic skeleton of bis[2-amino-4-phenyl-5-thiazolyl] disulfides were synthesized in a straightforward manner from acetophenones. 2-Amino-4-phenyl-1,3-thiazoles were prepared by the reaction of thiourea with substituted acetophenones in the presence of iodine which were then converted to the title compounds. All the compounds were subjected to preliminary evaluation for their biological activity against Gram positive and Gram negative bacteria. Some of the assayed compounds showed marked activity against Bacillus cereus and Pseudomonas aeruginosa.
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  • Quantification of Terbutaline in Pharmaceutical Formulation and Human Serum by Adsorptive Stripping Voltammetry at a Glassy Carbon Electrode
    Amr Mohamed Beltagi, Hana Salah El-Desoky, Mohamed Metwalli Ghoneim
    2007 Volume 55 Issue 7 Pages 1018-1023
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1018
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    The electrochemical oxidative behavior of terbutaline at the glassy carbon electrode was studied in a series of the Britton-Robinson buffer of pH 2—11. Cyclic and square-wave voltammograms of terbutaline at the pH values ≤9 exhibited a single irreversible anodic peak. A fully validated, simple, sensitive and precise square-wave adsorptive anodic stripping voltammetric procedure was described for the determination of terbutaline in bulk form, tablets and human serum. For 5×10−8 M bulk terbutaline a mean recovery of 98.78±0.94% (n=5) was achieved following its preconcentration by adsorptive accumulation onto the glassy carbon electrode at a +0.15 V (vs. Ag/AgCl/KCls) for 180 s. Limit of detection of 6×10−9 M and limit of quantitation of 2×10−8 M terbutaline were achieved in the bulk form or its formulations (Bricanyl® tablets). The described square-wave adsorption anodic stripping voltammetric procedure was successfully applied for the determination of terbutaline in human serum following medium exchange. Limit of detection of 1.41×10−8 M (3.173 ng ml−1) and limit of quantitation of 4.70×10−8 M (10.575 ng ml−1) were achieved in human serum with a mean recovery of 98.11±1.13%.
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  • Design, Synthesis, and Antiangiogenic Effects of a Series of Potent Novel Fumagillin Analogues
    Hong Woo Lee, Chin Sung Cho, Sung Kwon Kang, Yong Sang Yoo, Jae Soo Sh ...
    2007 Volume 55 Issue 7 Pages 1024-1029
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1024
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    A series of fumagillin analogues containing the C6-substituted cinnamoyl moiety were designed, synthesized, and evaluated for antiangiogenic activity. Among them, 4-hydroxyethoxy-cinnamoyl fumagillol (4a) and 4-hydroxyethoxy-3,5-dimethoxycinnamoyl fumagillol (4d) exhibited more potent anti-proliferation activity in CPAE and HUVEC cells with low cytotoxicity in vitro. These compounds are presently under further pharmacological evaluation studies.
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  • Effect of DNA on Filament Formation of Tau Microtubule-Binding Domain: Structural Dependence of DNA
    Rie Hikosou, Yasuko Kurabayashi, Michiko Doumoto, Kaoru Hoshitoku, Fum ...
    2007 Volume 55 Issue 7 Pages 1030-1033
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1030
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    To examine whether or not DNA accelerates the paired helical filament (PHF) formation of tau, the effect of various types of DNAs on filament formations of three-repeated and four-repeated microtubule-binding domains (3RMBD and 4RMBD, respectively) of tau protein was investigated by monitoring the change of thioflavin S fluorescence intensity, that is parallel to the filament formation. Consequently, the followings were clarified: 1) the structurally rigid double-stranded DNA such as poly(dG-dC) or calf thymus DNA has the high potency of promoting the filament formations of 3RMBD and 4RMBD, 2) the filament formation of 3RMBD was more promoted than that of 4RMBD, due to the intermolecular dimer formation of 3RMBD, 3) the DNA-promoted filament formations of these MBDs were temperature-dependent, and the single-stranded DNA such as poly(dA) or poly(dT) reversely protected 4RMBD from the molecular assembly at 20 °C. These are the first report on the function of DNA for the PHF formation of tau protein.
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  • Medicinal Flowers. XVI. New Dammarane-Type Triterpene Tetraglycosides and Gastroprotective Principles from Flower Buds of Panax ginseng
    Masayuki Yoshikawa, Sachiko Sugimoto, Seikou Nakamura, Hayaka Sakumae, ...
    2007 Volume 55 Issue 7 Pages 1034-1038
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1034
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    The oligoglycoside fraction from the flower buds of Panax ginseng C. A. MEYER (Araliaceae) was found to show protective effects on ethanol-induced gastric mucosal lesions in rats. From the oligoglycoside fraction, new dammarane-type triterpene tetraglycosides, floralginsenosides M, N, O, and P, were isolated together with the major oligoglycosides ginsenoside Rd and Re. The structures of the new floralginsenosides were elucidated on the basis of chemical and physicochemical evidence. Ginsenoside Rd (protopanaxadiol 3,20-O-bisdesmoside) exhibited inhibitory effects on ethanol- and indomethacin-induced gastric mucosal lesions in rats.
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  • Synthesis of the Metabolites of 4-(2-Methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide (KRP-197/ONO-8025)
    Ichiro Araya, Takeshi Tsubuki, Tatsuhiro Saito, Makoto Numata, Hiroyuk ...
    2007 Volume 55 Issue 7 Pages 1039-1043
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1039
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    We synthesized the six presumed metabolites (2—7) of 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide [KRP-197/ONO-8025, 1], a urinary incontinence therapeutic agent, in order to confirm the structures of the metabolites. Metabolite (2) was synthesized via glucuronidaion of compound (1) and methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-α-D-glucopyranuronate. Metabolite (3) was synthesized via 3-(tert-butoxycarbonyl)-2-methyl-1,3-imidazolidine-4,5-dione. Metabolites (4—7) were synthesized via 4-amino-2-diphenylbutanamide, respectively. The structures of the metabolites (2—7) in humans were identified by means of synthesis of the authentic compounds.
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  • Synthesis of Diphenylmethyl Analogues and Their Affinity for the Melanocortin-4 Receptor and the Serotonin Transporter
    Dai Nozawa, Taketoshi Okubo, Takaaki Ishii, Shigeyuki Chaki, Shigeru O ...
    2007 Volume 55 Issue 7 Pages 1044-1050
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1044
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    While examining antagonists of the melanocortin-4 receptor (MC4 receptor), we found that compound 12b, containing a diphenylmethyl moiety, had a relatively high affinity for the MC4 receptor. When diphenylmethyl analogues were further examined, compounds 12c and 18 were also found to exhibit a high affinity for the MC4 receptor (IC50=46.7 nM and 33.2 nM, respectively). Furthermore, compound 12c was also found to show a high affinity for the serotonin transporter (IC50=10.7 nM). Here, we describe the synthesis and biological evaluation of various diphenylmethyl analogues in relation to their actions on the MC4 receptor and the serotonin transporter.
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  • Determination of the Absolute Configuration of Sialic Acids in Gangliosides from the Sea Cucumber Cucumaria echinata
    Fumiaki Kisa, Koji Yamada, Tomofumi Miyamoto, Masanori Inagaki, Ryuich ...
    2007 Volume 55 Issue 7 Pages 1051-1052
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1051
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    Enantiomeric pairs of sialic acid, D- and L-NeuAc (N-acetylneuraminic acid), were converted to D- and L-arabinose, respectively, by chemical degradation. Using this method, the absolute configuration of the sialic acid residues, NeuAc and NeuGc (N-glycolylneuraminic acid), in the gangliosides from the sea cucumber Cucumaria echinata was determined to be the D-form. Although naturally occurring sialic acids have been believed to be the D-form on the basis of biosynthetic evidence, this is the first report of the determination of the absolute configuration of the sialic acid residues in gangliosides using chemical methods.
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  • Synthesis and Evaluation of 2-Nonylaminopyridine Derivatives as PPAR Ligands
    Shinya Usui, Hiroki Fujieda, Takayoshi Suzuki, Naoaki Yoshida, Hidehik ...
    2007 Volume 55 Issue 7 Pages 1053-1059
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1053
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    To find novel PPAR ligands, we prepared several 3-{3 or 4-[2-(nonylpyridin-2-ylamino)ethoxy]phenyl}propanoic acid derivatives which were designed based on the structure of our previous PPARγ ligand 1. In PPAR binding affinity assays, compound 4, which had an ethoxy group at the C-2 position of the propanoic acid of 1, showed selective binding affinity for PPARγ. Compound 3, with an ethyl group at the C-2 position, was found to be a PPARα/γ dual ligand. Compound 6, the meta isomer of 1, has been shown to be a PPARα ligand. The introduction of methyl (7) and ethyl (8) groups to the C-2 position of the propanoic acid of 6 further improved PPARα-binding potency. In cell-based transactivation assay, compounds 3 and 4 showed dual-agonist activity toward PPARα and PPARγ. Compound 6 was found to be a triple agonist and compound 8 proved to be a selective PPARα agonist. In the human hypodermic preadipocyte differentiation test, it was demonstrated that the maximal activity of compounds 3 and 4 was higher than that of rosiglitazone.
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  • Lipase-Catalyzed Asymmetric Synthesis of Desprenyl-carquinostatin A and Descycloavandulyl-lavanduquinocin
    Tominari Choshi, Yoshinari Uchida, Yukiko Kubota, Junko Nobuhiro, Mits ...
    2007 Volume 55 Issue 7 Pages 1060-1064
    Published: 2007
    Released on J-STAGE: July 01, 2007
    DOIhttps://doi.org/10.1248/cpb.55.1060
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    An asymmetric synthesis of the core carbazole structure, 6-desprenyl-carquinostatin 3 and 6-descycloavandulyl-lavanduquinocin 3, toward a total synthesis of carquinostatin A (1) and lavanduquinocin (2), has been established. Lipase QLM (Meito) catalyzed enantioselective acetylation of the racemic alcohol 6 gave the (−)-acetate 7 and the (+)-alcohol 6 with high enantioselectivity. The absolute stereochemistry of the (−)- and (+)-alcohol 6 have been determined to be R- and S-configurations, respectively, by the advanced Mosher method. In the same manner, the (−)-acetate 13 and the (+)-alcohol 12 have been obtained from the racemic alcohol 12. The (R)-(−)-acetate 13, derived from the (R)-(−)-acetate 7, was the same as the (−)-acetate 13, which has been determined to be (R)-configuration. Oxidation of the (R)-(−)-acetate 13 followed by hydrolysis afforded (R)-(−)-6-desprenyl-carquinostatin [and (R)-(−)-6-descycloavandulyl-lavanduquinocin] 3. In addition, oxidation of the (S)-(+)-alcohol 12 provided (S)-(+)-3, which is the enantiomer of 6-desprenyl-carquinostatin A (R)-(−)-3.
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