Synthesis and Evaluation of the Cytotoxicities of Tetraindoles: Observation that the 5-Hydroxy Tetraindole (SK228) Induces G2 Arrest and Apoptosis in Human Breast Cancer Cells

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• 作者：Wen-Shan Li ; Chie-Hong Wang ; Shengkai Ko ; Tzu Ting Chang ; Ya Ching Jen ; Ching-Fa Yao ; Shivaji V. More ; Shu-Chuan Jao
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 23, 2012
• 年：2012
• 卷：55
• 期：4
• 页码：1583-1592
• 全文大小：430K
• 年卷期：v.55,no.4(February 23, 2012)
• ISSN：1520-4804

文摘

Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogues, tetraindoles 1鈥?b>15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G₂-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.