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NF-κB regulation by bisbenzylisoquinoline alkaloids in human T cells: a structure–activity relationship study

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Abstract

Suppressive potencies of tetrandrine, isotetrandrine, fangchinoline, berbamine, dauricine, cepharanthine, and armepavine on expression and activation of NF-κB in MOLT-4 cells, MOLT-4/DNR cells, peripheral blood mononuclear cells (PBMCs) of healthy subjects and PBMCs of dialysis patients were compared. In MOLT-4 cells, the suppressive potencies evaluated by the IC50 values were isotetrandrine > cepharanthine > tetrandrine > dauricine > fangchinoline > berbamine or armepavine. In MOLT-4/DNR cells, the order was isotetrandrine > tetrandrine > cepharanthine > fangchinoline > dauricine > berbamine or armepavine. In PBMCs of healthy subjects, the order was isotetrandrine > dauricine > fangchinoline > tetrandrine > cepharanthine > berbamine or armepavine. In PBMCs of dialysis patients, the order was isotetrandrine > fangchinoline > tetrandrine > cepharanthine > dauricine > berbamine or armepavine. Among them, isotetrandrine showed the strongest inhibitory effects on the expression of NF-κB and p-NF-κB in these cells. Accordingly, both 7- and 12-substitutions are suggested to influence the suppressive potency of bisbenzylisoquinoline alkaloids, though 7-substitution is likely to have less contribution. Bisbenzylisoquinoline alkaloid seems to be more suitable than monobenzylisoquinoline alkaloid to serve as a lead compound. Bisbenzylisoquinoline alkaloids with an 18-membered ring formed by two oxygen bridges seem to be superior to those with one oxygen. However, the binding sites of two oxygen bridges on the phenyl ring appear to have limited influence. These findings provide further insight into structure–activity relationships to the development of active analogs of this promising class of drugs for the treatment of diseases mediated by abnormalities of T cell activation.

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (15K08081), Research Project for Practice Development of National TCM Clinical Research Bases (JDZX2015194), Japan China Sasakawa Medical Fellowship (2017816) and State Scholarship Fund of China Scholarship Council (201808420024).

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Authors and Affiliations

  1. Department of Pharmacy, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, PR China

    Wencheng Xu & Shuhe Chen

  2. Institute of Traditional Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, PR China

    Wencheng Xu & Shuhe Chen

  3. Department of Nephrology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, PR China

    Xiaoqin Wang

  4. Division of Pharmacy, Kanagawa-ken Keiyukai Keiyu Hospital, Kanagawa, Japan

    Junichi Kusano, Ryusei Yamamoto & Seiichi Hayashi

  5. Division of Nephrology, Kanagawa-ken Keiyukai Keiyu Hospital, Kanagawa, Japan

    Hiroto Matsuda, Yoshikazu Hara & Yoshiaki Fujii

  6. Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    Sachiko Tanaka, Kentaro Sugiyama, Haruki Yamada & Toshihiko Hirano

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  1. Wencheng Xu
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  2. Shuhe Chen
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  3. Xiaoqin Wang
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  11. Kentaro Sugiyama
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  13. Toshihiko Hirano
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Correspondence to Kentaro Sugiyama.

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Xu, W., Chen, S., Wang, X. et al. NF-κB regulation by bisbenzylisoquinoline alkaloids in human T cells: a structure–activity relationship study. Med Chem Res 29, 2123–2129 (2020). https://doi.org/10.1007/s00044-020-02624-2

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  • DOI: https://doi.org/10.1007/s00044-020-02624-2

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