γ‐Cyclodextrin as Inhibitor of the Precipitation Reaction between Berberine and Glycyrrhizin in Decoctions of Natural Medicines: Interaction Studies of Cyclodextrins with Glycyrrhizin and Glycyrrhetic Acid by 1H‐NMR Spectroscopy and Molecular‐Dynamics Calculation |
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Authors: | Miyoko Kamigauchi Kazuko Kawanishi Makiko Sugiura Hirofumi Ohishi Toshimasa Ishida |
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Institution: | 1. Kobe Pharmaceutical University, Motoyama Kitamachi, Higashinadaku, Kobe 658‐8558, Japan, (phone: +81‐78‐441‐7540;2. fax: +81‐78‐441‐7541);3. Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki Osaka 569‐1094, Japan |
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Abstract: | To prevent the precipitation reaction between glycyrrhizin ( 1 ) and berberine ( 3 ) in the decoctions of Glycyrrhiza/Coptis rhizome or Glycyrrhiza/Phellodendron bark, the presence of cyclodextrin (CD) in the mixture was proven to be effective. The preventing effect decreased in the order γ‐CD>β‐CD, and no effect was observed for α‐CD. On the other hand, the extraction degree of 1 from the natural medicine Glycyrrhia was considerably increased in the presence of γ‐CD, γ‐CD being much more effective than α‐ or β‐CD. Thus, the blocking effect of CD on the precipitate formation between 1 and 3 is suggested to be primarily dependent on the stability of the inclusion complex of the CD with 1 . To establish the structure of such a preferred inclusion complex, the interactions of 1 with β‐ and γ‐CDs were investigated by 1H‐NMR spectroscopy and molecular‐dynamics (MD) calculations. The 1H‐NMR measurements showed that the increase in solubility of 1 in H2O is dependent on the degree of its inclusion into the CD, which depends on the molecular size of the CD. The MD calculations suggested that the H‐bond interactions are sufficiently strong to form a stable 1 /γ‐CD] complex, in which the lipophilic rings C, D, and E of 1 are fully inserted into the molecular cavity of γ‐CD, thus forming a kind of structure covered by a hydrophilic molecular capsule, while such an interaction mode is impossible for α‐ or β‐CD. |
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Keywords: | γ ‐Cyclodextrins Berberine Inhibitors Glycyrrhetic acid NMR Spectroscopy Glycyrrhizin Molecular‐dynamics calculations Inclusion complexes |
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