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Investigational New Drugs

, Volume 29, Issue 1, pp 1–8 | Cite as

Structure-activity relationships between the Aconitum C20-diterpenoid alkaloid derivatives and the growth suppressive activities of Non-Hodgkin’s lymphoma Raji cells and human hematopoietic stem/progenitor cells

  • Masaharu Hazawa
  • Kenji Takahashi
  • Koji Wada
  • Takao Mori
  • Norio Kawahara
  • Ikuo KashiwakuraEmail author
PRECLINICAL STUDIES

Summary

The anti-tumor properties of novel derivatives prepared from Aconitum C20-diterpenoid alkaloid, which show the least toxicity among the Aconitum alkaloids, were investigated in the Non-Hodgkin’s lymphoma cell line Raji cells. Two novel Aconitum C20-diterpenoid alkaloid derivatives, 11-m-Trifluorometylbenzoyl (Mb)-pseudokobuisne and 11-Anisoyl (As)-pseudokobusine, showed significant suppressive effects and their 50% inhibitory concentrations were 2.2 μg/ml and 2.4 μg/ml against Raji cells, respectively. Both compounds have the same structure except for a functional group in the C-11 position. One of the active compounds, 11-Mb-pseudokobusine, clearly inhibited the phosphorylation of extracellular signal-regulated kinase, induced enhanced phosphoinositide 3 kinase phosphorylation and led to the subsequent accumulation of G1 and/or sub G1 phase in Raji cells. In addition, no significant suppressive effects on the growth of human CD34+ hematopoietic stem/progenitor cells (HSPC) were observed by 11-Mb-pseudokobusine which showed a strong suppressive activity on the growth of Raji cells, whereas 11-As-pseudokobusine also a showed significantly suppressive effect on the growth of HSPC. Therefore, the atisine type structure characteristic of C20-diterpenoid alkaloids plays a very important role in the pharmacological properties. In particular, the C-11 residues are an important component for the anti-tumor properties and for the lower toxicity to hematopoiesis.

Keywords

Aconitum C20-diterpenoid alkaloid Raji cells Hematopoietic stem/progenitor cells (HSPC) Structure activity relationships (SAR) 

Notes

Acknowledgments

This work was supported by a KAKENHI Grant-in-Aid for Exploratory Research (No. 19659300 IK). This work also received the support from a Grant for Priority Research on Issues of Great Urgency Designated by the President of Hirosaki University (2007) and a Grant for Hirosaki University Institutional Research (2008).

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Masaharu Hazawa
    • 1
  • Kenji Takahashi
    • 1
  • Koji Wada
    • 2
  • Takao Mori
    • 3
  • Norio Kawahara
    • 3
  • Ikuo Kashiwakura
    • 1
    Email author
  1. 1.Department of Radiological Life SciencesHirosaki University Graduate School of Health SciencesHirosakiJapan
  2. 2.School of PharmacyHokkaido Pharmaceutical UniversityOtaruJapan
  3. 3.Research CenterNorth Japan Chemical Inc.EniwaJapan

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