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Bioactivity inspired C19-diterpenoid alkaloids for overcoming multidrug-resistant cancer

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Abstract

The pharmacological activities of C19-diterpenoid alkaloids are related to their basic skeletons (e.g., aconitine-type or lycoctonine-type). Also, few studies have been reported on the chemosensitizing effects of diterpenoid alkaloids. Consequently, this study was aimed at determining the chemosensitizing effects of synthetic derivatives of lycoctonine-type C19-diterpenoid alkaloids on a P-glycoprotein (P-gp)-overexpressing multidrug-resistant (MDR) cancer cell line KB-VIN. The acyl-derivatives of delpheline and delcosine showed moderate cytotoxicity against chemosensitive cancer cell lines. Among non-cytotoxic synthetic analogs (1−14), several derivatives effectively and significantly sensitized MDR cells by interfering with the drug transport function of P-gp to three anticancer drugs, vincristine, paclitaxel, and doxorubicin. The chemosensitizing effect of derivatives 2, 4, and 6 on KB-VIN cells against vincristine were more potent than 5 μM verapamil, and derivatives 4 and 13 were more effective than 5 μM verapamil for paclitaxel. Among them, 2 in particular increased the sensitivity of KB-VIN cells to vincristine by 253-fold.

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Acknowledgements

We appreciate critical comments, suggestions, and editing of the manuscript by Dr. Susan L. Morris-Natschke (UNC-CH). This study was supported in part by NIH grant CA177584 from the National Cancer Institute awarded to K.H.L. as well as the Eshelman Institute for Innovation, Chapel Hill, North Carolina, awarded to M.G.

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Author notes

  1. Koji Wada and Masuo Goto contributed equally to this work.

Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 4-1, Maeda 7-jo 15-choume, Teine-ku, Sapporo, 006-8585, Japan

    Koji Wada & Hiroshi Yamashita

  2. Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA

    Masuo Goto, Emika Ohkoshi & Kuo-Hsiung Lee

Authors
  1. Koji Wada
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  2. Masuo Goto
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  3. Emika Ohkoshi
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  4. Kuo-Hsiung Lee
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  5. Hiroshi Yamashita
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Correspondence to Koji Wada.

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Wada, K., Goto, M., Ohkoshi, E. et al. Bioactivity inspired C19-diterpenoid alkaloids for overcoming multidrug-resistant cancer. J Nat Med 76, 796–802 (2022). https://doi.org/10.1007/s11418-022-01629-y

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  • DOI: https://doi.org/10.1007/s11418-022-01629-y

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