Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Reviews
  • Takayoshi Awakawa
    2021 Volume 69 Issue 5 Pages 415-420
    Published: May 01, 2021
    Released: May 01, 2021
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    Natural products are an important source of medicinal seeds. The discovery of novel biosynthetic enzymes from nature is important for their use as biocatalysts for the enzymatic synthesis of useful natural products. In addition, genetics and structural biology developments have enabled the engineering of enzymes for the production of unnatural analogs of bioactive natural products. In this review, I describe the recent research on these two topics, the exploitation of a novel secondary metabolite enzyme involved in the biosynthesis of the sulfonamide natural product antibiotic SB-203208, and the production of unnatural bioactive depsipeptides by reconstruction of the modular enzyme assembly lines in the microbial host.

  • Bai-Lin Li, Jie Yuan, Jie-Wei Wu
    2021 Volume 69 Issue 5 Pages 421-431
    Published: May 01, 2021
    Released: May 01, 2021
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    Rosa laevigata Michx., a medicinal and edible plant in China, has exerted a variety of medicinal values and health benefits. This present review aims to achieve a comprehensive and up-to-date investigation in the phytochemistry and pharmacology of R. laevigata. According to these findings in the literature, approximately 123 chemical ingredients covering triterpenoids, flavonoids, tannis, lignans and polysaccharides, have been characterized from various parts of this species. Among these isolates, 77 triterpenoids have been isolated and thus regarded as the primary and characteristic substance. Based on the chemical structures, most of the obtained triterpenoids can be classified into polyhydroxy triterpenoids and readily divided into four categories: ursane-type, oleanane-type, lupinane-type, as well as seco-triterpenoids. The crude extracts and the purified compounds have demonstrated various pharmacological effects in vitro and in vivo, such as antioxidant activity, immunomodulatory effect, anti-inflammatory effect, liver protection, kidney protection, cardiovascular protection, neuroprotective effect and improvement of diabetic cataract. Noticeably, these pharmacological results of R. laevigata provide evidences for its traditional uses. In addition, these different chemical ingredients existing in the title plant may have synergistic effects. In conclusion, the chemical profiles, including ingredients and structures, together with the modern pharmacological properties have been adequately summarized. These evidences have revealed this plant to be a valuable source for therapeutic foodstuff and more attention should be paid to a better utilization of this plant.

    Editor’s picks

    This present review aims to achieve a comprehensive and up-to-date investigation in the phytochemistry and pharmacology of Rosa laevigata Michx.. To date, phytochemical investigation has exposed the presence of triterpenoids, flavonoids, tannins, ligands and polysaccharides in this plant. The crude extracts and the purified compounds have demonstrated various pharmacological effects in vitro and in vivo. In conclusion, the chemical profiles together with the modern pharmacological properties have been adequately summarized. These evidences have revealed this plant to be a valuable source for therapeutic foodstuff and more attention should be paid to a better utilization of this plant.

  • Evi Sulastri, Ronny Lesmana, Muhammad Sulaiman Zubair, Khaled M. Elami ...
    2021 Volume 69 Issue 5 Pages 432-443
    Published: May 01, 2021
    Released: May 01, 2021
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    Ulvan is a natural sulfated polysaccharide obtained from marine green algae composed of 3-sulfated rhamnoglucuronan as the main component. It has a unique chemical structure that rich of L-rhamnosa, D-glucuronic acid, and L-iduronic acid. Ulvan has a similar structure to glycosaminoglycans (GAGs) in mammals including chondroitin sulfate, dermatan sulfate, and heparan sulfate that has broad range applications for many years. Here, we provide an overview of ulvan based hydrogels for biomedical applications. Hydrogels are one of ulvan advances in polymer science for application in drug delivery, tissue engineering, and wound healing. This review presented an overview about functional information of ulvan based hydrogels and the promising potential in biomedicals collected from published papers in Scopus, PubMed, and Google Scholar. Other important aspects concerning properties, hydrogel-forming mechanisms, and ulvan based hydrogel developments were reported as well. As conclusion, ulvan showed interesting properties in forming hydrogels and promising advances in biomedical applications.

Communication to the Editor
  • Jinyan Jiang, Xinyang Li, Takahiro Mori, Takayoshi Awakawa, Ikuro Abe
    2021 Volume 69 Issue 5 Pages 444-446
    Published: May 01, 2021
    Released: May 01, 2021
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    Supplementary material

    Structurally diverse fungal meroterpenoids are promising drug seed compounds. To obtain unnatural, novel meroterpene scaffolds, we tested combinatorial biosynthesis by co-expressing functionally distinct terpene cyclase (TPC) genes, pyr4, ascF, andB, or cdmG, with the biosynthetic genes for the production of a TPC substrate, (10′R)-epoxyfarnesyl-dimethylorsellinic acid-3,5-methyl ester, in Aspergillus oryzae NSAR1 as a heterologous host. As a result, all of the tested TPCs afforded the same two novel mono-cyclization products. This study provides important information on the substrate scope of the TPCs, and will contribute to the production of unnatural, novel molecules for future drug discovery.

    Editor’s picks

    Structurally diverse fungal meroterpenoids are promising drug seed compounds. To obtain unnatural, novel meroterpene scaffolds, the authors tested combinatorial biosynthesis by co-expressing functionally distinct terpene cyclase (TPC) genes, pyr4, ascF, andB, or cdmG, with the biosynthetic genes for the production of a TPC substrate, (10’R)-epoxyfarnesyl-dimethylorsellinic acid-3,5-methyl ester, in Aspergillus oryzae NSAR1 as a heterologous host. As a result, all of the tested TPCs afforded the same two novel mono-cyclization products. This study provides important information on the substrate scope of the TPCs, and will contribute to the production of unnatural, novel molecules for future drug discovery.

Regular Articles
  • Agata Ishikawa, Hiroshi Takasaki, Atsushi Sakurai, Takuma Katayama, Ko ...
    2021 Volume 69 Issue 5 Pages 447-455
    Published: May 01, 2021
    Released: May 01, 2021
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    This study aimed to compare the manufacturability and granule and tablet properties of green fluidized bed granulation (GFBG) and of direct compression (DC). Acetaminophen was used as a low compactability model drug. The process time of GFBG to produce final mixtures was comparable to that of DC, and thus GFBG could be considered a simple process. DC could not produce 30% drug load tablets owing to poor granule flowability, whereas no problems were observed in the GFBG tableting process up to 80% of drug load. Tablets prepared with GFBG showed higher tensile strength than those prepared using DC. Compactability evaluation results show that the yield pressure of the granules prepared with GFBG was significantly lower than that of DC, suggesting that the granules prepared with GFBG were easily plastically deformed. Moreover, tablets prepared with GFBG showed fast disintegration, which was faster than that of DC. We conclude that GFBG produces granules with higher drug content and desired physicochemical properties at low cost.

  • Shin Ijitsu, Yohei Hoashi, Koji Hori, Kazuto Okimoto, Toshiya Kai, Miy ...
    2021 Volume 69 Issue 5 Pages 456-463
    Published: May 01, 2021
    Released: May 01, 2021
    [Advance publication] Released: February 23, 2021
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    The purpose of this research was firstly to prepare solifenacin succinate functional particles embedded in a gelling–swelling layer (PEGS) so as to achieve both taste-masking of the unpleasant taste of the drug and rapid drug elution, and secondly to incorporate these PEGS into orally disintegrating tablets (ODTs). In in vitro dissolution tests, initial drug release from the prepared PEGS could be suppressed to less than 1% after 2 min and increased to more than 85% after 30 min by adjusting the composition of the PEGS, in particular the thickness of the outer water-penetration control layer which contains a water-insoluble polymer. For the preparation of ODTs containing PEGS, a semi-direct compression method was adopted in order to prevent damage to the PEGS by processes such as granulation or compaction. The use of a fibre-shaped microcrystalline cellulose with poor fluidity improved the content uniformity of the ODTs, as the crystal fibres became entangled with the PEGS and other additives. The use of spherical mannitol with a hollow structure produced by spray drying imparted relatively high hardness and rapid disintegration properties to the final ODTs containing PEGS, which were tableted using a low compression force. There was no significant difference in the drug-release profiles of the optimally formulated ODTs containing PEGS tableted at different compression forces. The ODTs containing PEGS maintained a drug-release lag time sufficient for taste-masking of solifenacin succinate.

    Editor’s picks

    The authors developed solifenacin succinate functional drug particles embedded in a gelling–swelling layer (PEGS) made of a three-layer structure consisting of a core drug layer, a gelling–swelling layer, by which both adequate taste-masking of drug and rapid drug elution were successfully achieved. They also optimized incorporation of above PEGS into orally disintegrating tablets (ODTs), by usage of a fibre-shaped microcrystalline cellulose with poor fluidity, which improved the content uniformity of the ODTs, as the crystal fibres became entangled with the PEGS and other additives. Overall, this taste masking system is so unique and propose new platform for taste masking formulation.

  • Toshio Morikawa, Yoshiaki Manse, Fenglin Luo, Haruko Fukui, Yamato Ino ...
    2021 Volume 69 Issue 5 Pages 464-471
    Published: May 01, 2021
    Released: May 01, 2021
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    Supplementary material

    A methanol extract from the underground part of Calanthe discolor Lindl. (Orchidaceae) demonstrated significant proliferative activity on human hair follicle dermal papilla cells (HFDPC, % of control: 120.8 ± 0.2%) at 100 µg/mL against HFDPC. Through bioassay-guided separation of the extract, a new indole glycoside named 6′-O-β-D-apiofuranosylindican (1) was isolated along with six known compounds (27) including three indole glycosides. The stereostructure of 1 was elucidated based on its spectroscopic properties and chemical characteristics. Among the isolates, 1 (110.0 ± 1.0%), glucoindican (3, 123.9 ± 6.8%), and calanthoside (4, 158.6 ± 7.1%) showed significant proliferative activity at 100 µM. Furthermore, the active indole glycosides (1, 3, and 4) upregulated the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-7 (FGF-7) mRNA and protein in HFDPC, which could be the mechanism of their proliferative activity.

    Editor’s picks

    A methanol extract from the underground part of Calanthe discolor Lindl. (Orchidaceae) demonstrated significant proliferative activity against human hair follicle dermal papilla cells (HFDPC). Through bioassay-guided separation of the extract, a new indole glycoside named 6′-O-b-D-apiofuranosylindican was isolated along with six known compounds including three indole glycosides. Among the isolates, three indole glycoside such as 6′-O-b-D-apiofuranosylindican, glucoindican, and calanthoside showed significant proliferative activity. Furthermore, these active indole glycosides upregulated the expression of VEGF and FGF-7 mRNA and protein in HFDPC, which could be the mechanism of their proliferative activity.

  • Bai-ling Sun, En-bo Cai, Yan Zhao, Yu Wang, Li-min Yang, Jing-Yao Wang
    2021 Volume 69 Issue 5 Pages 472-480
    Published: May 01, 2021
    Released: May 01, 2021
    [Advance publication] Released: February 25, 2021
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    Arctigenin (ARG), a natural lignans compound isolated from Arctium lappa L. In this study, the anti-tumor effect of ARG on prostate cancer cell PC-3M and the mechanism of apoptosis and autophagy induced by phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway were discussed, and further confirmed by the joint treatment of ARG and PI3K inhibitor LY294002. Here, the effect of ARG on cell viability was evaluated in PC-3M cells by Cell Counting Kit-8 reagent (CCK-8) assay. After the treatment of ARG, colony formation assay was used to detect the anti-proliferation effect. Annexin V-fluoresceine isothiocyanate/propidium iodide (FITC/PI) kit and 4′,6-diamidino-2-phenylindole (DAPI) staining were used to detect the apoptosis level, and cell cycle changes were analyzed by flow cytometry. The expression of autophagy was detected by acridine orange staining. In addition, the expression levels of apoptosis and autophagy-related proteins were analyzed by Western blot. The result showed that different concentrations of ARG inhibited the proliferation of PC-3M cells. DAPI staining and flow cytometry showed that ARG induced PC-3M cell apoptosis and arrested cell in G0/G1 phase. Acridine orange staining showed that ARG induced autophagy in PC-3M cells. Western blot experiments showed that ARG inhibited the expression of Bcl-2, promoted the expression of Bax and cleaved caspase-3. At the same time, the expression of autophagy-related proteins LC3B-II and Beclin-1 increased after ARG treatment, but P62 decreased. In addition, further studies have shown that treatment with LY294002 enhanced the effects of ARG on the expression of proteins associated with apoptosis and autophagy, indicating that ARG may induce apoptosis and autophagy through PI3K/Akt/mTOR pathway.

  • Kenji Mori, Eri Usuzaka, Takeshi Oshizaka, Chihiro Takei, Hiroaki Todo ...
    2021 Volume 69 Issue 5 Pages 481-487
    Published: May 01, 2021
    Released: May 01, 2021
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    Ionic liquid (IL) was prepared by mixing lidocaine and ibuprofen as a cation and anion, respectively, at various ratios. We determined the permeation of both compounds from the IL through a silicone membrane selected as a model biological membrane, and mathematically analyzed the permeation data from the viewpoint of the thermodynamic activities of lidocaine, ibuprofen, and the IL. As a result, IL and ibuprofen diffusely permeated through the membrane in the case of applying IL preparations with a molar fraction of ibuprofen of 0.5 or higher. The IL was thought to separate into lidocaine and ibuprofen in the receiver. On the other hand, when applying IL preparations with a molar fraction of lidocaine of 0.5 or higher, IL and lidocaine permeated. The permeation rate of IL itself was maximized when the applied IL was prepared using equimolar amounts of lidocaine and ibuprofen, and it decreased when the fraction of lidocaine or ibuprofen increased by more than 0.5. Their membrane permeation rates increased with an increase in their activity, and no more increase was found when the drugs were saturated in the IL. These membrane permeation profiles reflected well the mathematically calculated ones according to the concept of activity.

  • Yusuke Sasano, Aoto Yamaichi, Ryota Sasaki, Shota Nagasawa, Yoshiharu ...
    2021 Volume 69 Issue 5 Pages 488-497
    Published: May 01, 2021
    Released: May 01, 2021
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    Supplementary material

    Four distinctive sets of optimum nitroxyl radical/copper salt/additive catalyst combinations have been identified for accommodating the aerobic oxidation of various types of primary alcohols to their corresponding aldehydes. Interestingly, less nucleophilic catalysts exhibited higher catalytic activities for the oxidation of particular primary allylic and propargylic alcohols to give α,β-unsaturated aldehydes that function as competent Michael acceptors. The optimum conditions identified herein were successful in the oxidation of various types of primary alcohols, including unprotected amino alcohols and divalent-sulfur-containing alcohols in good-to-high yields. Moreover, N-protected alaninol, an inefficient substrate in the nitroxyl radical/copper-catalyzed aerobic oxidation, was oxidized in good yield. On the basis of the optimization results, a guideline for catalyst selection has been established.

    Editor’s picks

    This manuscript reports aerobic oxidation of primary alcohols into aldehydes with nitroxyl radical/copper catalysis. The reaction method reported herein features that the optimum nitroxyl radical/copper salt catalyst combinations differ depending on the substrate. To express this feature, the catalytic reaction field is represented as a circus tent with three shapes of windows, namely, circle, triangle, and square. Copper plates with different nitroxyl radicals are placed under each of the windows, which indicates different nitroxyl radical/copper salt catalyst combinations. Different alcohol substrates are represented in different forms, namely, sphere, tetrahedron, cube. The sphere, tetrahedral, and cubic alcohols pass through the circular, triangular, and square windows, respectively, to be oxidized into aldehydes.

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