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Structure–activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents

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Abstract

Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. However, little information has been reported on the antiproliferative effects of the diterpenoid alkaloid constituents of Aconitum and Delphinium plants. C-1 and 14 esterifications of delcosine (1) were carried out to provide 39 new diterpenoid alkaloid derivatives (3–14, 16–29, 3a–7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a). Selected compounds (3–14, 16–29, 3a–7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a) were evaluated for antiproliferative activity against three to five human tumor cell lines including triple-negative breast cancer (TNBC) and P-glycoprotein (P-gp) overexpressing multidrug-resistant (MDR) subline. Several newly synthesized delcosine derivatives (6, 7, 13, 13a, 13b) showed substantial suppressive effects against all human tumor cell lines tested. In contrast, the natural alkaloids (1, 31, 33) showed no effect. Most of the active compounds were delcosine derivatives with two specific substitution patterns—C-1 and C-1,14. In particular, 1-acyldelcosine derivative (5–7) displayed more potency than 1,14-diacyldelcosine derivatives (5a–7a). These acylated alkaloid derivatives caused accumulation of TNBC cells at sub-G1 within 24 h. 1-Acylation of 1 appears to be critical for producing antiproliferative activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents.

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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 KHL as well as the Eshelman Institute for Innovation, Chapel Hill, NC, USA awarded to MG.

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  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, Takahiro Shimizu, Nami Kusanagi, Megumi Mizukami, Yuji Suzuki & Hiroshi Yamashita

  2. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA

    Masuo Goto, Kang-Po Li & Kuo-Hsiung Lee

  3. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, 40402, Taiwan

    Kuo-Hsiung Lee

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  1. Koji Wada
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  2. Masuo Goto
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  3. Takahiro Shimizu
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  5. Megumi Mizukami
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  9. Hiroshi Yamashita
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Correspondence to Koji Wada.

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Wada, K., Goto, M., Shimizu, T. et al. Structure–activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents. J Nat Med 73, 789–799 (2019). https://doi.org/10.1007/s11418-019-01331-6

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  • DOI: https://doi.org/10.1007/s11418-019-01331-6

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