Synthesis and biological evaluation of sulfur-containing shikonin oxime derivatives as potential antineoplastic agents
Synthesis and biological evaluation of sulfur-containing shikonin oxime derivatives as potential antineoplastic agents
复制标题
潜在抗肿瘤药物含硫紫草肟衍生物的合成及生物学评价
DOI：
10.1016/j.ejmech.2017.11.031
复制
发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Li, Shao-Shun
中科院分区：
文献类型：
--
作者：
Huang, Guang;Zhao, Hui-Ran;Li, Shao-Shun
作为我们开发高效和潜在安全的抗肿瘤药物的研究的继续，我们合成了一组45个含硫紫草素肟衍生物，并评价了它们对人结肠癌(HCT-15)、胃癌(MGC-803)、肝癌(Bel7402)、乳腺癌细胞(MCF-7)和人皮肤成纤维细胞(HSF)的体外细胞毒活性。所有化合物对HCT-15细胞具有较强的选择性杀伤活性，对正常HSF细胞无明显毒性，部分化合物对HCT-15、MGC-803和Bel7402细胞有较强或较强的杀伤活性。抗肿瘤活性最强的化合物9M对人癌细胞的IC50为0.27+/-0.02~9.23+/-0.12mU。构效关系(SARS)研究表明，侧链上取代基的性质对体外抗肿瘤活性有重要影响。此外，一氧化氮释放研究表明，这些肟衍生物产生的一氧化氮数量相对较少。此外，细胞机制研究表明，化合物9M可使细胞周期停滞于G1期，并诱导HCT-15细胞发生强烈的凋亡反应。此外，Western印迹研究表明，化合物9M通过下调Bcl2、上调Bax、caspase3和9的表达而诱导细胞凋亡。因此，化合物9M具有潜在的抗肿瘤作用。(C)2017年爱思唯尔·马森公司。版权所有。
As a continuation of our research on developing potent and potentially safe antineoplastic agents, a set of forty five sulfur-containing shikonin oxime derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human colon cancer (HCT-15), gastric carcinoma (MGC-803), liver (Bel7402), breast (MCF-7) cancer cells and human skin fibroblast (HSF) cells. All the synthesized compounds exhibited potent cytotoxic activity selectively towards HCT-15 cells and did not display apparent toxicity to the normal HSF cells, some of which were more or comparatively effective to the parent compound against HCT-15, MGC-803 and Bel7402 cells. The most active agent 9m displayed high potency against human cancer cells with IC50 ranging from 0.27 +/- 0.02 to 9.23 +/- 0.12 mu M. The structure-activity relationships (SARs) studies suggested that the nature of substituent group in the side chain is important for antitumor potency in vitro. Additionally, nitric oxide release studies revealed that the amount of nitric oxide generated from these oxime derivatives was relatively low. Furthermore, cellular mechanism investigations indicated that compound 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Moreover, western blot studies revealed that compound 9m induced apoptosis through the down-regulation of Bcl-2 and up-regulation of Bax, caspase 3 and 9. For all these reasons, compound 9m hold promising potential as antineoplastic agent. (C) 2017 Elsevier Masson SAS. All rights reserved.