Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonol-derived hybrid molecules against Plasmodium falciparum and multidrug-resistant human leukemia cells
Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonol-derived hybrid molecules against Plasmodium falciparum and multidrug-resistant human leukemia cells
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DOI：
10.1016/j.ejmech.2014.01.043
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发表时间：
2014-03-21
影响因子：
6.7
通讯作者：
Tsogoeva, Svetlana B.
中科院分区：
文献类型：
--
作者：
Reiter, Christoph;Karagoez, Aysun Capci;Tsogoeva, Svetlana B.
疟疾和癌症每年导致数百万人死亡。为了对抗这两种疾病，重要的是新的药物活性化合物具有克服癌症和恶性疟原虫菌株中的多药耐药性的能力。为了寻找与其母体化合物相比具有改善的性质的有效抗癌和抗疟疾杂合物，合成了一系列新的基于1，2，4-三恶烷的杂合物，其掺入了埃贡醇和/或二茂铁片段，并在体外针对恶性疟原虫菌株、CCRF CEM细胞和多药耐药P-糖蛋白过表达CEM/ADR 5000细胞进行了测试。青蒿琥酸同源二聚体12和13是抗恶性疟原虫活性最高的化合物（IC 50分别为0.32和0.30 nM），而新的杂交体7（1，2，4-trioxane ferrocene egonol），9（1，2，4-三氧杂环已烷二茂铁）和11（青蒿琥酯酸艾格诺）对CCRF CEM细胞表现出显着的细胞毒性（IC 50分别为0.07、0.25和0.18 μ M）。杂合分子7中的三个部分1，2，4-三恶烷、二茂铁和伊古酚的协同增效作用是显著的，并且明显强于杂合分子9（1，2，4-三恶烷二茂铁）和11（青蒿琥酯酸伊古酚），杂合分子9（1，2，4-三恶烷二茂铁）和11（青蒿琥酯酸伊古酚）仅包含所考虑的三种母体化合物中的两种。有趣的是，混合物9含有1，2，4-三恶烷和二茂铁片段已被证明是最有效的研究中的杂交体对测试的多药耐药白血病CEM/ADR 5000细胞（IC 50为0.57 μ M），并具有2.34的交叉耐药性的程度。(C)2014年Elsevier Masson SAS。All rights reserved.
Malaria and cancer cause the death of millions of people every year. To combat these two diseases, it is important that new pharmaceutically active compounds have the ability to overcome multidrug resistance in cancer and Plasmodium falciparum strains. In search of effective anti-cancer and anti-malaria hybrids that possess improved properties compared to their parent compounds, a series of novel 1,2,4-trioxane-based hybrids incorporating egonol and/or ferrocene fragments were synthesized and tested in vitro against P. falciparum strains, CCRF CEM cells and the multidrug-resistant P-glycoprotein-over-expressing CEM/ADR5000 cells. The most active compounds against P. falciparum strains were artesunic acid homodimers 12 and 13 (IC50 of 0.32 and 0.30 nM, respectively), whereas novel hybrids 7 (1,2,4-trioxane ferrocene egonol), 9 (1,2,4-trioxane ferrocene) and 11 (artesunic acid egonol) showed a remarkable cytotoxicity toward CCRF CEM cells (IC50 of 0.07, 0.25 and 0.18 mu M, respectively). A cooperative and synergistic effect of the three moieties 1,2,4-trioxane, ferrocene and egonol in hybrid molecule 7 is significant and is obviously stronger than in hybrids 9 (1,2,4-trioxane ferrocene) and 11 (artesunic acid egonol), which comprises of only two of the three considered parent compounds. Interestingly, hybrid 9 containing a 1,2,4-trioxane and a ferrocene fragment has shown to be the most effective among the studied hybrids against the tested multidrug-resistant leukemia CEM/ADR5000 cells (IC50 of 0.57 mu M) and possesses a degree of cross-resistance of 2.34. (C) 2014 Elsevier Masson SAS. All rights reserved.