Synthesis and evaluation of 3-ylideneoxindole acetamides as potent anticancer agents.

Abstract

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.

• Authors: Chun-Tang Chiou, Wei-Chun Lee, Jiahn-Haur Liao, Jing-Jy Cheng, Lie-Chwen Lin, Chih-Yu Chen, Jen-Shin Song, Ming-Hsien Wu, Kak-Shan Shia, Wen-Tai Li
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 98 Pg. 1-12 (Jun 15 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 25988923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Acetamides
• Antineoplastic Agents
• Indoles

Topics

• Acetamides (chemistry)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Mice
• Mice, Inbred BALB C
• Models, Molecular
• Xenograft Model Antitumor Assays