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有机化学
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有机化学 ›› 2010, Vol. 30 ›› Issue (12): 1865-1869. 上一篇    下一篇

研究论文

新型化学修饰siRNAs的设计、合成及生物活性研究

李祎亮1,2，任开环1，李洪明3，王菊仙1，邹美香2，何红伟1，邵荣光1，王玉成*,1   

  1. (1中国医学科学院医药生物技术所 北京 100050)
    (2天津药物研究院 天津市新药设计与发现重点实验室 天津 300193)
    (3天津中医药大学 天津 300193)
  • 收稿日期:2010-02-10 修回日期:2010-05-08 发布日期:2010-07-19
  • 通讯作者: 李祎亮 E-mail:langyil@sina.com
  • 基金资助:

    “重大新药创制”科技重大专项分项目

Design, Synthesis and Biological Activity of Novel Chemical Modified siRNAs

Li Yiliang1,2 Ren Kaihuan1 Li Hong-ming3 Wang Juxian1 Zou Meixiang2 He Hongwei1 Shao Rongguang1 Wang Yucheng*,1   

  1. (1 Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050)
    (2Tianjin Key Laboratory of Molecular Design & Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193)
    (3 Tianjin University of Traditional Chinese Medical, Tianjin 300193)
  • Received:2010-02-10 Revised:2010-05-08 Published:2010-07-19

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被引次数

1

以含取代基团的苯酚和氯代环氧丙烷为原料, 经多步反应合成了4种含芳香结构的化学修饰单体, 针对靶向Mdm2 mRNA序列的siRNA, 在其3 末端加入不同化学修饰的单体制备获得9个siRNAs. 采用四甲基偶氮唑盐(MTT)法对所合成的siRNAs进行体外抗肿瘤活性、稳定性测试, 结果显示化学修饰的siRNA8, siRNA11, siRNA15对人乳腺癌MCF-7细胞的活性和核酸酶稳定性均有显著提高, 其中siRNA11体外对RNA水解酶的半衰期提高了10倍.

关键词: 化学修饰, siRNA, 抗肿瘤活性

Four aromatic chemically modified units were synthesized by multi-step reactions from substituted phenol and 3-chloro-1,2-epoxypropane. These compounds were incorporated into the 3 -overhang regions of siRNAs targeting mdm2 mRNA to prepare nine modified siRNA molecules. The antitumor activity of the synthesized siRNAs was evaluated by methylthiazolyl tetrazolium (MTT) method. The nuclease stability of the individual siRNAs was tested in vitro. Based on the preliminary experimental results and com-pared with the natural siRNA, three modified siRNA molecules (siRNA8, siRNA11 and siRNA15) showed remarkable improvement in bioactivity and stability. siRNA11 was shown to be 2-fold more potent and 10-fold increase in half-time of nuclease resistance.

Key words: chemical modification, siRNA, anticancer activity