Chiou Chun-Tang, Lee Wei-Chun, Liao Jiahn-Haur, Cheng Jing-Jy, Lin Lie-Chwen, Chen Chih-Yu, Song Jen-Shin, Wu Ming-Hsien, Shia Kak-Shan, Li Wen-Tai
National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11221, Taiwan.
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
Eur J Med Chem. 2015 Jun 15;98:1-12. doi: 10.1016/j.ejmech.2015.04.062. Epub 2015 May 2.
Indirubin, an active component in the traditional Chinese medicine formula Danggui Longhui Wan, shows promising anticancer effects. Meisoindigo is an analog derived from indirubin, which is less toxic and appears to be even more potent against cancer. In considering meisoindigo as a structural template for the development of new drugs, we designed and synthesized a series of 3-ylideneoxindole acetamides as novel anticancer agents. The acetamides were then evaluated for in vitro and in vivo anticancer activities. The 3-ylideneoxindole acetamides were found to have better anticancer activity than was indirubin-3'-oxime in several cancer cell lines and also displayed a spectrum of activity similar to that of the drug candidate roscovitine, a CDK inhibitor. Among the 3-ylideneoxindole acetamides, compound 10 showed particularly good efficacy. Cell cycle analysis further revealed that compound 10 arrested cells in the G1 phase and caused an increase in the sub-G1 population, indicating that the apoptosis pathway had been induced. In addition, exposure of cells to compound 10 led to the upregulation of the cell-cycle regulator cyclin D1, which was sustained at a high level. In contrast, the same compound induced a short-term elevation in the level of cyclin E, which was followed by a rapid decrease and the attenuation of Rb phosphorylation. Furthermore, a docking model suggests that compound 10 binds to the active site of CDK4. In testing the therapeutic potency of compound 10 on CT26-xenografted BALB/c mice, a significant reduction in tumor size comparable to that of cisplatin was found when administrated via the i.p. route. The mice presented no loss of body weight, indicating that this compound possesses low toxicity. In the future, we are planning in vivo investigations of these new active anticancer agents to better elucidate active mechanisms at the cellular level and thus benefit the development of anticancer therapies.
靛玉红是中药当归龙荟丸中的一种活性成分，具有显著的抗癌作用。美索靛蓝是从靛玉红衍生而来的类似物，毒性较小，对癌症的抑制作用似乎更强。在将美索靛蓝作为开发新药的结构模板时，我们设计并合成了一系列3-亚苄基氧化吲哚乙酰胺作为新型抗癌剂。然后对这些乙酰胺进行了体外和体内抗癌活性评估。发现在几种癌细胞系中，3-亚苄基氧化吲哚乙酰胺比靛玉红-3'-肟具有更好的抗癌活性，并且还表现出与候选药物罗可辛（一种CDK抑制剂）相似的活性谱。在3-亚苄基氧化吲哚乙酰胺中，化合物10显示出特别好的疗效。细胞周期分析进一步表明，化合物10使细胞停滞在G1期，并导致亚G1期细胞群体增加，表明诱导了细胞凋亡途径。此外，细胞暴露于化合物10导致细胞周期调节因子细胞周期蛋白D1上调，并持续维持在高水平。相比之下，相同的化合物诱导细胞周期蛋白E水平短期升高，随后迅速下降以及Rb磷酸化减弱。此外，对接模型表明化合物10与CDK4的活性位点结合。在测试化合物10对CT26异种移植BALB/c小鼠的治疗效力时，通过腹腔注射给药时，发现肿瘤大小显著减小，与顺铂相当。小鼠体重没有减轻，表明该化合物毒性低。未来，我们计划对这些新型活性抗癌剂进行体内研究，以更好地阐明细胞水平的活性机制，从而有利于抗癌疗法的发展。
