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.
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.
Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori, 036-8564, Japan.
Masaharu
M
Hazawa
Kenji
K
Takahashi
Koji
K
Wada
Takao
T
Mori
Norio
N
Kawahara
Ikuo
I
Kashiwakura
D031841:Aconitum / Q000737:chemistry*; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002244:Carbon; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology; D008517:Phytotherapy; D013329:Structure-Activity Relationship
D000470:Alkaloids; D001952:Bridged-Ring Compounds; D002070:Butadienes; D004224:Diterpenes; D009570:Nitriles; D010616:Phenanthrenes; C113580:U 0126; C111430:pseudokobusine; D002244:Carbon; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases