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

  • Koji WadaEmail author
  • Masuo Goto
  • Takahiro Shimizu
  • Nami Kusanagi
  • Megumi Mizukami
  • Yuji Suzuki
  • Kang-Po Li
  • Kuo-Hsiung Lee
  • Hiroshi Yamashita
Original Paper

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 (314, 1629, 3a7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a). Selected compounds (314, 1629, 3a7a, 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 (57) displayed more potency than 1,14-diacyldelcosine derivatives (5a7a). 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.

Keywords

Diterpenoid alkaloid Delcosine Delcosine derivatives Antiproliferative agents Structure–activity relationship 

Notes

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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Copyright information

© The Japanese Society of Pharmacognosy 2019

Authors and Affiliations

  • Koji Wada
    • 1
    Email author
  • Masuo Goto
    • 2
  • Takahiro Shimizu
    • 1
  • Nami Kusanagi
    • 1
  • Megumi Mizukami
    • 1
  • Yuji Suzuki
    • 1
  • Kang-Po Li
    • 2
  • Kuo-Hsiung Lee
    • 2
    • 3
  • Hiroshi Yamashita
    • 1
  1. 1.Department of Medicinal Chemistry, Faculty of Pharmaceutical SciencesHokkaido University of ScienceSapporoJapan
  2. 2.Natural Products Research Laboratories, UNC Eshelman School of PharmacyUniversity of North CarolinaChapel HillUSA
  3. 3.Chinese Medicine Research and Development CenterChina Medical University and HospitalTaichungTaiwan

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