Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death
- 作者：Ritu Aneja ; Surya N. Vangapandu ; Manu Lopus ; Vijaya G. Viswesarappa ; Neerupma Dhiman ; Akhilesh Verma ; Ramesh Chandra ; Dulal Panda and Harish C. Joshi
- 关键词：Cell cycle ; Mitotic arrest ; Anticancer ; Tubulin-binding
- 刊名：Biochemical Pharmacology
- 出版年：2006
- 期刊代码：2_00062952
- 类别：pha
- 出版时间：14 August 2006
- 卷：72
- 期：4
- 页码：415-426
- 文件大小：4449 K
摘要
We have previously identified the naturally occurring non-toxic antitussive phthalideisoquinoline alkaloid, noscapine as a tubulin-binding agent that arrests mitosis and induces apoptosis. Here we present high-yield efficient synthetic methods and an evaluation of anticancer activity of halogenated noscapine analogs. Our results show that all analogs display higher tubulin-binding activity than noscapine and inhibit proliferation of human cancer cells (MCF-7, MDA-MB-231 and CEM). Surprisingly, the bromo-analog is 40-fold more potent than noscapine in inhibiting cellular proliferation of MCF-7 cells. The ability of these analogs to inhibit cellular proliferation is mediated by cell cycle arrest at the G2/M phase, in that all analogs except 9-iodonoscapine, caused selective mitotic arrest with a higher efficiency than noscapine followed by apoptotic cell death as shown by immunofluorescence and quantitative FACS analyses. Furthermore, our results reveal the appearance of numerous fragmented nuclei as evidenced by DAPI staining. Thus, our data indicate a great potential of these compounds for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers.