Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10β-(2-hydroxyethyl)deoxoartemisinin
Antimalarial and antitumor evaluation of novel C-10 non-acetal dimers of 10β-(2-hydroxyethyl)deoxoartemisinin
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DOI：
10.1021/jm030974c
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发表时间：
2004-02-26
影响因子：
7.3
通讯作者：
O'Neill, PM
中科院分区：
文献类型：
--
作者：
Jeyadevan, JP;Bray, PG;O'Neill, PM
以关键三烷醇10 β-（2-羟乙基）脱氧青蒿素（9 b）为原料，合成了四个系列的C-10非缩醛二聚体。所有的二聚体制备显示出有效的低纳摩尔抗疟活性对K1和HB 3株恶性疟原虫。测定的最有效的化合物是磷酸二聚体14 a，其比母体药物青蒿素的效力高50倍以上，比临床使用的缩醛蒿甲醚的效力高约15倍。与它们对疟疾寄生虫的有效活性相反，除了三恶烷磷酸酯二聚体14 a和14 b之外，几乎所有的二聚体都表达差的抗癌活性，三恶烷磷酸酯二聚体14 a和14 b在NCI 60人细胞系筛选中相对于一系列癌细胞系表达纳摩尔生长抑制（GI（50））值。在HL 60细胞中对这些二聚体进行的进一步详细研究表明，磷酸酯二聚体（14 a和14 b）比抗癌剂阿霉素更有效。有趣的是，磷酸酯单体9 c和9d，在低纳摩尔区域相对于恶性疟原虫具有抗疟活性，即使在毫摩尔区域的浓度下作为抗癌剂也是无活性的。这一观察结果强调了两个三恶烷单位的高抗增殖活性的重要性，我们提出，这种类型的二聚体中的接头的性质在赋予有效的抗癌活性中起着至关重要的作用。
Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10beta-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. In contrast to their potent activity versus malaria parasites, virtually all of the dimers expressed poor anticancer activity apart from the trioxane phosphate ester dimers 14a and 14b, which expressed nanomolar growth inhibitory (GI(50)) values versus a range of cancer cell lines in the NCI 60 human cell line screen. Further detailed studies on these dimers in vitro in HL60 cells demonstrate that both phosphate ester dimers (14a and 14b) are more potent than the anticancer agent doxorubicin. Interestingly, phosphate ester monomers 9c and 9d, antimalarially active in the low nanomolar region versus P. falciparum, are inactive as anticancer agents even at concentrations in the millimolar region. This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity.