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
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
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DOI：
10.1007/s10637-009-9327-4
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发表时间：
2011-02-01
影响因子：
3.4
通讯作者：
Kashiwakura, Ikuo
中科院分区：
文献类型：
--
作者：
Hazawa, Masaharu;Takahashi, Kenji;Kashiwakura, Ikuo
研究了乌头类生物碱中毒性最小的C-20-二萜生物碱类化合物在非霍奇金淋巴瘤细胞系Raji细胞中的抗肿瘤作用。两种新的乌头C-20-二萜生物碱衍生物11-m-三氟甲酰基(Mb)-伪可可可可碱和11-异山梨基(AS)-可可可可碱对Raji细胞有明显的抑制作用，其50%抑制浓度分别为2.2mU/ml和2.4mU/ml。除了C-11位上的官能团外，这两个化合物具有相同的结构。其中活性化合物11-Mb-Passokobusine能明显抑制细胞外信号调节蛋白激酶的磷酸化，诱导肌醇磷脂3蛋白的磷酸化增强，并导致Raji细胞的G1期和/或亚G1期积聚。此外，对Raji细胞生长有较强抑制作用的11-Mb-伪柯布辛对人CD34(+)造血干/祖细胞(HSPC)的生长没有明显的抑制作用，而11-AS对HSPC的生长也有明显的抑制作用。因此，C-20-二萜生物碱的蒂斯汀类型结构特征对其药理性质具有重要的影响。特别是，C-11残基是抗肿瘤性能和较低的造血毒性的重要组成部分。
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 mu g/ml and 2.4 mu g/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.