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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and antiproliferative activity of novel symmetrical alkylthio- and alkylseleno-imidocarbamates.
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Synthesis and antiproliferative activity of novel symmetrical alkylthio- and alkylseleno-imidocarbamates.

机译：新型对称的烷基硫代和烷基硒代亚氨基氨基甲酸酯的合成及其抗增殖活性。

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The study described here concerns the synthesis of a series of thirty new symmetrically substituted imidothiocarbamate and imidoselenocarbamate derivatives and their evaluation for antitumoral activity in vitro against a panel of five human tumor cell lines: breast adenocarcinoma (MCF-7), colon carcinoma (HT-29), lymphocytic leukemia (K-562), hepatocarcinoma (Hep-G2), prostate cancer (PC-3) and one non-malignant mammary gland-derived cell line (MCF-10A). The GI(50) values for eighteen of the compounds were below 10 muM in at least one cell line. Two cancer cells (MCF-7 and HT-29) proved to be the most sensitive to five compounds (1b, 2b, 3b, 4b and 5b), with growth inhibition in the nanomolar range, and compounds 1b, 3b, 7b, 8b and 9b gave values of less than 1 muM. In addition, all of the aforementioned compounds exhibited lower GI(50) values than some of the standard chemotherapeutic drugs used as references. The results also reveal that the nature of the aliphatic chain (methyl is better than benzyl) at the selenium position and the nature of the heteroatom (Se better than S) have a marked influence on the antiproliferative activity of the compounds. These findings reinforce our earlier hypothesis concerning the determinant role of the selenomethyl group as a scaffold for the biological activity of this type of compound. Considering both the cytotoxic parameters and the selectivity index (which was compared in MCF-7 and MCF-10A cells), compounds 2b and 8b (with a selenomethyl moiety) displayed the best profiles, with GI(50) values ranging from 0.34 nM to 6.07 muM in the five cell lines tested. Therefore, compounds 2b and 8b were evaluated by flow cytometric analysis for their effects on cell cycle distribution and apoptosis in MCF-7 cells. 2b was the most active, with an apoptogenic effect similar to camptothecin, which was used as a positive control. Both of them provoked cell cycle arrest leading to the accumulation of cells in either G(2)/M and S phase. These two compounds can therefore be considered as the most promising candidates for the development of novel generations of antitumor agents.
机译：这里描述的研究涉及一系列三十种新的对称取代的亚氨基硫代氨基甲酸酯和亚氨基硒代氨基甲酸酯衍生物的合成，以及它们在体外对一组五种人类肿瘤细胞系的抗肿瘤活性的评估：乳腺腺癌（MCF-7），结肠癌（HT- 29），淋巴细胞白血病（K-562），肝癌（Hep-G2），前列腺癌（PC-3）和一种非恶性乳腺衍生细胞系（MCF-10A）。在至少一种细胞系中，十八种化合物的GI（50）值低于10μM。事实证明，两种癌细胞（MCF-7和HT-29）对五种化合物（1b，2b，3b，4b和5b）最敏感，生长抑制在纳摩尔范围内，而化合物1b，3b，7b，8b和9b给出的值小于1μM。此外，所有上述化合物的GI（50）值均低于用作参考的某些标准化学治疗药物。结果还表明，在硒位置的脂族链的性质（甲基比苄基更好）和杂原子的性质（Se比S更好）对化合物的抗增殖活性有显着影响。这些发现加强了我们先前关于硒甲基作为此类化合物生物活性支架的决定性作用的假说。考虑到细胞毒性参数和选择性指数（在MCF-7和MCF-10A细胞中进行了比较），化合物2b和8b（具有硒代甲基部分）显示出最佳的分布图，GI（50）值范围为0.34 nM至在测试的五个细胞系中为6.07μM。因此，通过流式细胞术分析评价化合物2b和8b对MCF-7细胞中细胞周期分布和凋亡的影响。 2b是最活跃的，其凋亡作用类似于喜树碱，后者被用作阳性对照。他们两个都引起细胞周期停滞，导致细胞在G（2）/ M和S期积累。因此，可以将这两种化合物视为开发新一代抗肿瘤剂的最有希望的候选者。

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