RRC ID 18558
Author Hazawa M, Takahashi K, Wada K, Mori T, Kawahara N, Kashiwakura I.
Title 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.
Journal Invest New Drugs
Abstract The anti-tumor properties of novel derivatives prepared from Aconitum C(20)-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 C(20)-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 C(20)-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.
Volume 29(1)
Pages 1-8
Published 2011-2
DOI 10.1007/s10637-009-9327-4
PMID 19784550
MeSH Aconitum / chemistry* Alkaloids / chemistry* Alkaloids / pharmacology* Blotting, Western Bridged-Ring Compounds / pharmacology Butadienes / pharmacology Carbon Cell Line, Tumor Cell Proliferation / drug effects Cyclin-Dependent Kinase 2 / metabolism Diterpenes / chemistry* Diterpenes / pharmacology* Diterpenes / therapeutic use Enzyme Activation / drug effects Extracellular Signal-Regulated MAP Kinases / metabolism G1 Phase / drug effects Hematopoietic Stem Cells / cytology* Hematopoietic Stem Cells / drug effects Humans Lymphoma, Non-Hodgkin / drug therapy Lymphoma, Non-Hodgkin / enzymology Lymphoma, Non-Hodgkin / pathology* Nitriles / pharmacology Phenanthrenes / pharmacology Phytotherapy Structure-Activity Relationship
IF 2.663
Times Cited 11
Human and Animal Cells RAJI (RCB1647)