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Compound–compound interaction analysis of baicalin and berberine derivatives in aqueous solution

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Abstract

Baicalin and berberine are biologically active constituents of the crude drugs Scutellaria root and Coptis rhizome/Phellodendron bark, respectively. Baicalin and berberine are reported to combine together as a 1:1 complex that forms yellow precipitates by electrostatic interaction in decoctions of Kampo formulae containing these crude drugs. However, the structural basis and mechanism for the precipitate formation of this compound–compound interaction in aqueous solution remains unclarified. Herein, we searched for berberine derivatives in the Coptis rhizome that interact with baicalin and identified the chemical structures involved in the precipitation formation. Precipitation assays showed that baicalin formed precipitates with berberine and coptisine but not with palmatine and epiberberine. Thus, the 2,3-methylenedioxy structure may be crucial to the formation of the precipitates, and electrostatic interaction is necessary but is not sufficient. In this multicomponent system experiment, palmatine formed a dissociable complex with baicalin and may competitively inhibit the formation of berberine and coptisine precipitation with baicalin. Therefore, the precipitation formed by berberine and baicalin was considered to be caused by the aggregation of the berberine–baicalin complex, and the 2,3-methylenedioxy structure is likely crucial to the aggregation of the complex.

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Acknowledgements

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Funding

This work was supported in part by Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research (YU).

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Authors and Affiliations

  1. Division of Natural Medicines, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan

    Yoshinori Uekusa, Chiharu Tanioka, Kenjiro Nakamoto, Riina Tsutsumi, Chihiro Iida, Naoto Enshu, Takehiro Nishimura, Fumiyuki Kiuchi & Haruhisa Kikuchi

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  1. Yoshinori Uekusa
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  2. Chiharu Tanioka
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  3. Kenjiro Nakamoto
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  4. Riina Tsutsumi
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  6. Naoto Enshu
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  7. Takehiro Nishimura
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  8. Fumiyuki Kiuchi
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  9. Haruhisa Kikuchi
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Contributions

YU, FK, and HK directed the project. YU designed the study conception. YU and TN designed the experiments, and YU, CT, KN, RT, CI, and NE conducted the experiments, analyzed, and interpreted the results. YU, FK, TN, and HK wrote the manuscript.

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Correspondence to Yoshinori Uekusa or Haruhisa Kikuchi.

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Uekusa, Y., Tanioka, C., Nakamoto, K. et al. Compound–compound interaction analysis of baicalin and berberine derivatives in aqueous solution. J Nat Med (2024). https://doi.org/10.1007/s11418-024-01804-3

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