Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 60, Issue 6
Displaying 1-16 of 16 articles from this issue
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Review
  • Investigation of Innovative Synthesis of Biologically Active Compounds on the Basis of Newly Developed Reactions
    Toshio Honda
    Article type: Review
    2012 Volume 60 Issue 6 Pages 687-705
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.687
    JOURNAL FREE ACCESS
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    Synthesis of biologically active compounds, including natural products and pharmaceutical agents, is an important and interesting research area since the large structural diversity and complexity of bioactive compounds make them an important source of leads and scaffolds in drug discovery and development. Many structurally and also biologically interesting compounds, including marine natural products, have been isolated from nature and have also been prepared on the basis of a computational design for the purpose of developing medicinal chemistry. In order to obtain a wide variety of derivatives of biologically active compounds from the viewpoint of medicinal chemistry, it is essential to establish efficient synthetic procedures for desired targets. Newly developed reactions should also be used for efficient synthesis of desired compounds. Thus, recent progress in the synthesis of biologically active compounds by focusing on the development of new reactions is summarized in this review article.
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Regular Articles
  • Formation and Conformation of Baicalin–Berberine and Wogonoside–Berberine Complexes
    Jing-Rong Wang, Takashi Tanaka, Hong Zhang, Isao Kouno, Zhi-Hong Jiang
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 706-711
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.706
    JOURNAL FREE ACCESS
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    It is well-known that baicalin–berberine complex (1) precipitates in the water decoction of numerous Chinese Medicinal formulae containing Radix Scutellariae and Rhizoma Coptidis or Cortex Phellodendri. In the current study, ionic interaction between the carboxylate ion of baicalin and the quaternary ammonium ion of berberine was revealed to be responsible for the formation of 1 and wogonoside–berberine (2) by using FAB-MS and NMR titration experiments. In addition, nuclear Overhauser effect spectroscopy (NOESY) correlations observed in 1 and 2 suggested quite different conformation of the two complexes, which was further supported by the fact that the [α]D of the canadine obtained by reduction of 1 is of an opposite sign to that obtained from 2. Partition coefficients (n-octanol/water) determination demonstrated 12–20 times larger partition coefficient of each complex (1, 2) than that of each single compound (baicalin, wogonoside, and berberine), indicating the significant role of the formation of the complex in the bioavailability enhancement of these pharmacologically active constituents.
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  • Characterization Using LC/MS of the Absorption Compounds and Metabolites in Rat Plasma after Oral Administration of a Single or Mixed Decoction of Shaoyao and Gancao
    Lan Shen, Wen-Juan Cong, Xiao Lin, Yan-Long Hong, Rong-Wan Hu, Yi Feng ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 712-721
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.712
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    Shaoyao–Gancao decoction (SGD), a traditional Chinese formulation containing Paeoniae Radix (SY) and Glycyrrhizae Radix (GC), is commonly used to relieve abdominal pain. However, the absorption and metabolites of the characteristic constituents of the two herbs in vivo have been reported rarely. The purpose of this study was to investigate the compatibility rationality and the mechanism of the enhanced efficiency of SGD. A single or a mixed decoction (SG and S+G, respectively) was orally administered to rats. Blood samples were collected at different intervals following treatment and analyzed by liquid LC/MS. A total of fifteen ingredients (denoted as M1 to M15) were found in both rat plasma after treatment with the two decoctions. Furthermore, the proposed structures of the remained twelve ingredients were obtained except M9, M10 and M15. The quality of the ingredients in the rat plasma showed no significant difference between the two decoctions. However, the quantity of twelve ingredients differed greatly, indicating that the absorption of SG was greater than that of S+G except M7, M12 and M15. As the compositions associated with the efficacy of SG and S+G were inconsistent, the degree of the absorption of the 15 ingredients by the gastrointestinal tract were different, which caused a significantly enhanced efficacy of certain ingredients. This study presents an exploration of the mechanism behind the improved efficacy of individual components in traditional Chinese medicine therapies through combination with other components.
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  • Condensation of 2-Naphthol and Naphthalenediols with o-Dichlorobenzene in the Presence of Aluminum Halides
    Konstantin Yuryevich Koltunov, Aleksey Nikolaevich Chernov, Gubbi Kris ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 722-727
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.722
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    It is known that 1-naphthol, as a result of superelectrophilic (dicationic) activation in superacid media, is able to react with such deactivated aromatic compound as o-dichlorobenzene to give 4-(3,4-dichlorophenyl)-1-tetralone (2), which is a highly valuable intermediate in the synthesis of the antidepressant, sertraline (1) and other useful derivatives. However, the analogous reactivity of 2-naphthol and a variety of naphthalenediols towards o-dichlorobenzene has not been investigated thus far, although the corresponding tetralones, bearing dichlorophenyl moiety, could be of great pharmacochemical interest. In present work, we disclose that 1,5-, 1,6-, and 1,7- naphthalenediols (6a–c) react smoothly with o-dichlorobenzene in the presence of an excess of aluminum chloride or aluminum bromide to give the pairs of isomeric 4-(3,4-dichlorophenyl)- and 4-(2,3-dichlorophenyl)- 5-, 6-, and 7-hydroxy-1-tetralones (10a–c and 11a–c) in high overall yields. 2-Naphthol and 2,7-naphthalenediol (6d) exhibited comparatively lower reactivity, which however was sufficient to obtain the corresponding dichlorophenyl-2-tetralones in moderate yields. The mechanism of these reactions involving superelectrophilic dicationic or even tricationic intermediates, is discussed.
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  • New Triterpenoid Saponins from Fruit Specimens of Panax japonicus Collected in Toyama Prefecture and Hokkaido (2)
    Kouichi Yoshizaki, Morikazu Murakami, Hiroharu Fujino, Naotoshi Yoshid ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 728-735
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.728
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    Four new dammarane-type triterpenoid saponins, chikusetsusaponin FT1 (1), chikusetsusaponin FT2 (2), chikusetsusaponin FT3 (3), chikusetsusaponin FT4 (4), and six known triterpenoid saponins, chikusetsusaponin FK4 (8), chikusetsusaponin FK5 (9), chikusetsusaponin FK2 (10), chikusetsusaponin FK3 (11), chikusetsusaponin LN4 (12), and chikusetsusaponin IVa (14), were isolated from the fruits of Panax japonicus C. A. MEYER, collected in Toyama prefecture, Japan, and five new dammarane-type triterpenoid saponins, chikusetsusaponin FT1 (1), chikusetsusaponin FT3 (3), chikusetsusaponin FT4 (4), chikusetsusaponin FH1 (5), chikusetsusaponin FH2 (6), and eight known triterpenoid saponins, ginsenoside Re (7), chikusetsusaponin FK5 (9), chikusetsusaponin FK2 (10), chikusetsusaponin FK3 (11), chikusetsusaponin LN4 (12), 28-desglucosylchikusetsusaponin IVa (13), chikusetsusaponin IVa (14), and chikusetsusaponin V (15), were isolated from the fruits of P. japonicus C. A. MEYER, collected in Hokkaido, Japan. The structures of new chikusetsusaponins were elucidated on the basis of chemical and physicochemical evidences.
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  • Preparation of Natural Borneol/2-Hydroxypropyl-β-cyclodextrin Inclusion Complex and Its Effect on the Absorption of Tetramethylpyrazine Phosphate in Mouse
    Jianyu Su, Jianping Chen, Lin Li, Bing Li, Lei Shi, Hongmei Zhang, Xio ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 736-742
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.736
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    Natural borneol (NB)/2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex has been prepared, and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform infrared spectroscopy (FT-IR). The phase solubility and release of NB, and its effect on the absorption of tetramethylpyrazine phosphate (TMPP) in mice were also measured. The results demonstrated that NB could be efficiently loaded into HP-β-CD to form an inclusion complex at a mass ratio of 1 : 6, and the inclusion complex had different physicochemical characteristics from free NB. The profile of phase solubility displayed a typical AL-type, indicating the formation of 1 : 1 stoichiometric inclusion complex. Additionally, the stability of the inclusion complex was greatly improved compared with that of NB. The results of absorption of TMPP in mouse indicated that NB/HP-β-CD enhanced the absorption of TMPP and the concentration of TMPP in brain tissue, especially in the early period. Both TMPP plasma and brain concentration–time courses in mice were fitted to open two-compartment model with first-order absorption after oral administration of TMPP with NB/HP-β-CD. However, the use of NB/HP-β-CD did not change the in vivo behavior of TMPP. Our results suggest the application potential of NB/HP-β-CD inclusion in pharmaceutics.
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  • Synthesis of Novel Fatty-Acyl Gratisin Derivatives
    Makoto Tamaki, Takuji Harada, Kenta Fujinuma, Kazumasa Takanashi, Mits ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 743-746
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.743
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    To find candidates with high antimicrobial and low hemolytic activities, many gratisin (GR) analogues have been designed and synthesized. In the present account, we synthesized novel derivatives of GR having both the polycationic and fatty acyl groups, cyclo{-Val1-Orn2-Leu3-D-Phe4-Pro5-D-Lys6(X)-Val7-Orn8-Leu9-D-Phe10-Pro11-D-Lys12-} {X=-CO(CH2)6CH3 (1), -Lys-CO(CH2)6CH3 (2), -(Lys)2-CO(CH2)6CH3 (3), and -(Lys)3-CO(CH2)6CH3 (4)}, and examined the biological activities. Among them, we found that 2–4 have differential ionic interaction against the prokaryotic membrane and eukaryotic membrane. In other words, the dissociation with high antimicrobial activity and low hemolytic activity is caused by the addition of D-Lys6-{(Lys)n-CO(CH2)6CH3} residues at position 6 of [D-Lys6,12]-GR. Our findings should be helpful in finding drug candidates with high antimicrobial activity and low hemolytic activity that are capable of combating microbial resistance.
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  • Garlicnins B1, C1, and D, from the Fraction Regulating Macrophage Activation of Allium sativum
    Toshihiro Nohara, Yuka Kiyota, Toyonobu Sakamoto, Hideyuki Manabe, Mas ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 747-751
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.747
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    Several novel sulfides from acetone extracts of bulbs of garlic (Allium sativum L.), were identified and investigated. These were named garlicnins B1 (1), C1 (2), and D (3), and they were found to have the ability to control macrophage activation. Garlicnins B1 (1) and C1 (2) possess a new skeleton of cyclic sulfoxide and their structures of garlicnins B1 (1) and C1 (2) were characterized as 3,4-dimethyltetrahydrothiophene-S-oxide derivatives carrying the substitutions of a propenyl and a sulfenic acid, and an allyldithiine and a 1-propene-sulfenic acid (a), respectively. The mechanism of the proposed production of these compounds is discussed. Garlicnin D (3), dithiine-type, was estimated to be derived by addition of (a)+allyl thiosulfenic acid (b) derived from allicin. The identification of these novel sufoxides from onion and garlic accumulates a great deal of new chemistry to the Allium sulfide field, and future pharmacological investigations aid the development of natural, healthy foods and anti-cancer agents that could potentially prevent or combat disease.
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  • Medicinal Flowers. XXXVI.1) Acylated Oleanane-Type Triterpene Saponins with Inhibitory Effects on Melanogenesis from the Flower Buds of Chinese Camellia japonica
    Seikou Nakamura, Katsuyoshi Fujimoto, Souichi Nakashima, Takahiro Mats ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 752-758
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.752
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    Four acylated oleanane-type triterpene oligoglycosides, sanchakasaponins E–H, were isolated from the flower buds of Camellia japonica cultivated in Yunnan province, China, together with four known triterpene oligoglycosides. The chemical structures of the new triterpene oligoglycosides were elucidated on the basis of chemical and physicochemical evidence. The inhibitory effects of the triterpene oligoglycoside constituents on melanogenesis in theophylline-stimulated B16 melanoma 4A5 cells were investigated.
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  • The New Cassane-Type Diterpenes from Caesalpinia minax
    Guo-Xu Ma, Jing-Quan Yuan, Li Cao, Jun-Shan Yang, Xu-Dong Xu
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 759-763
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.759
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    Four new cassane-type diterpenes, Neocaesalpin S (1), Neocaesalpin T (2), Neocaesalpin U (3), and Neocaesalpin V (4) were isolated from Caesalpinia minax HANCE together with seven known compounds Neocaesalpin A (5), Neocaesalpin K (6), Neocaesalpin L (7), Neocaesalpin M (8), Neocaesalpin O (9), Neocaesalpin MP (10), and Magnicaesalpin (11). Their structures were elucidated on the basis of 1D- and 2D-NMR, MS, and circular dichroism (CD) analysis. Compounds 1–4 were tested against liver cancer (HepG-2) and breast cancer (MCF-7), and showed mild antiproliferative activity.
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  • Structural Modulation Study of Inhibitory Compounds for Ribonuclease H Activity of Human Immunodeficiency Virus Type 1 Reverse Transcriptase
    Hiroshi Yanagita, Satoshi Fudo, Emiko Urano, Reiko Ichikawa, Masakazu ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 764-771
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.764
    JOURNAL FREE ACCESS
    Supplementary material
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    Reverse transcriptase of human immunodeficiency virus type 1 (HIV-1) has two enzymatic functions. One of the functions is ribonuclease (RNase) H activity concerning the digestion of only RNA of RNA/DNA hybrid. The RNase H activity is an attractive target for a new class of anti-HIV drugs because no approved inhibitor is available now. In our previous studies, an agent bearing 5-nitro-furan-2-carboxylic acid ester core was found from chemical screening and dozens of the derivatives were synthesized to improve compound potency. In this work, some parts of the chemical structure were modulated to deepen our understanding of the structure–activity relationship of the analogous compounds. Several derivatives having nitro-furan-phenyl-ester skeleton were shown to be potent RNase H inhibitors. Attaching methoxy-carbonyl and methoxy groups to the phenyl ring increased the inhibitory potency. No significant cytotoxicity was observed for these active derivatives. In contrast, the derivatives having nitro-furan-benzyl-ester skeleton showed modest inhibitory activities regardless of attaching diverse kinds of functional groups to the benzyl ring. Both the modulation of the 5-nitro-furan-2-carboxylic moiety and the conversion of the ester linkage resulted in a drastic decrease in inhibitory potency. These findings are informative for designing potent inhibitors of RNase H enzymatic activity of HIV-1.
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  • In-Die Evaluation of Capping Tendency of Pharmaceutical Tablets Using Force-Displacement Curve and Stress Relaxation Parameter
    Hideya Nakamura, Yui Sugino, Satoru Watano
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 772-777
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.772
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    A novel in-die evaluation method of tablet capping tendency was proposed based on a force-displacement curve and stress relaxation parameter in a tableting process. In our previous study (Chem. Pharm. Bull., 59, 2011, Nakamura et al.), the phase diagram consisting of elastic recovery energy (Ee) and plastic deformation energy (Ep) of compressed powder, named as the Ee–Ep diagram, was proposed. However, it was found that capping tendency of tablets prepared by double-compression with multi-component powder formulations cannot be discriminated using the Ee–Ep diagram. To improve the capping discrimination ability, we here proposed a novel corrected phase diagram consisting of the Ee and an interparticle bonding parameter Eb(t), named as the Ee–Eb(t) diagram. The Eb(t) was proposed as a new parameter expressing strength of the interparticle bonding formed by the stress relaxation inside compressed powder. The Eb(t) was defined as a product of the Ep and the stress relaxation parameter Y(t), estimated from the force-displacement curve and the stress relaxation test. The capping discrimination ability of the diagrams was evaluated using a hierarchical-clustering analysis. The results exhibited that the capping tendency could be clearly discriminated using the proposed Ee–Eb(t) diagram at the double-compression and the multi-component powder formulations, as compared to the Ee–Ep diagram. This proposed diagram can be used for screening of the powder formulations to avoid the capping.
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  • Synthesis of Certain 2-Substituted-1H-benzimidazole Derivatives as Antimicrobial and Cytotoxic Agents
    Azza Taher Taher, Nadia Abdalla Khalil, Eman Mohamed Ahmed, Yasser Moh ...
    Article type: Regular Article
    2012 Volume 60 Issue 6 Pages 778-784
    Published: June 01, 2012
    Released on J-STAGE: June 01, 2012
    DOIhttps://doi.org/10.1248/cpb.60.778
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    A series of 2-substituted-1H-benzimidazole derivatives were synthesized and evaluated for antimicrobial, antifungal and cytotoxic activities. The results showed that all tested compounds showed potent antimicrobial activity against some species of Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi) and fungi (Candida albicans) with minimum inhibitory concentrations (MICs) lower than 0.016 µg/mL. In contrast, all tested compounds were inactive against Staphylococcus aureus (Gram-positive bacterium). The final targets were also tested for their antitumor activity in vitro on cervical carcinoma (HeLa) cell line. Eight of the test compounds displayed more potent cytotoxic effect than doxorubicin at nanomolar concentrations. Compounds 2c and 3c exerted the strongest cytoyoxic effect with IC50 15 and 13 nM, respectively.
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