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鬼臼毒素衍生物的合成及其抗肿瘤活性

胡昆, 周安飞, 蒋何菲, 许园元, 黄倩卉, 杨洁, 陈新, 任杰

胡昆, 周安飞, 蒋何菲, 许园元, 黄倩卉, 杨洁, 陈新, 任杰. 鬼臼毒素衍生物的合成及其抗肿瘤活性[J]. 中国药科大学学报, 2014, 45(1): 33-38. DOI: 10.11665/j.issn.1000-5048.20140105
引用本文: 胡昆, 周安飞, 蒋何菲, 许园元, 黄倩卉, 杨洁, 陈新, 任杰. 鬼臼毒素衍生物的合成及其抗肿瘤活性[J]. 中国药科大学学报, 2014, 45(1): 33-38. DOI: 10.11665/j.issn.1000-5048.20140105
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HU Kun, ZHOU Anfei, JIANG Hefei, XU Yuanyuan, HUANG Qianhui, YANG Jie, CHEN Xin, REN Jie. Synthesis and antitumor activities of podophyllotoxin derivatives[J]. Journal of China Pharmaceutical University, 2014, 45(1): 33-38. DOI: 10.11665/j.issn.1000-5048.20140105
Citation: HU Kun, ZHOU Anfei, JIANG Hefei, XU Yuanyuan, HUANG Qianhui, YANG Jie, CHEN Xin, REN Jie. Synthesis and antitumor activities of podophyllotoxin derivatives[J]. Journal of China Pharmaceutical University, 2014, 45(1): 33-38. DOI: 10.11665/j.issn.1000-5048.20140105
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鬼臼毒素衍生物的合成及其抗肿瘤活性

  • 常州大学制药与生命科学学院

基金项目: 国家自然科学基金资助项目(No.21202012)；2012江苏省“青蓝工程”资助项目；常州市基础研究计划(应用基础)资助项目(No.CJ20130021)

Synthesis and antitumor activities of podophyllotoxin derivatives

摘要

    摘要
  • 摘要: 以抗肿瘤天然产物鬼臼毒素为原料，对其C环修饰，经叠氮化、还原、加成、消除得到4β-异硫氰酸酯-4-脱氧鬼臼毒素，再与各种酰肼反应得到氨基硫脲衍生物，最后经环化得到一系列4β-(1，3，4-GFDA2二唑-2-氨基)-鬼臼毒素衍生物。前期研究表明当衍生物的R基团是甲基时，其对于HepG2细胞和HeLa细胞株的抗肿瘤活性高于鬼臼毒素，对正常细胞株L929和Vero的细胞毒性则低于依托泊苷、鬼臼毒素和氟尿嘧啶。在此基础上，本研究设计了一系列R基团为直链烷基或环烷取代基的衍生物，以期发现抗肿瘤活性更好、选择性较高、细胞毒性更低的化合物。利用MTT法，对于6种肿瘤细胞系Du-145、HeLa、A549、K562、K562/adr、HepG2测试合成化合物的体外细胞毒性。实验结果表明，化合物 6a ， 6b ， 6d 具有明显的抗肿瘤活性。
    Abstract: Starting with natural anticancer product podophyllotoxin, its C-ring was modified in five steps. Podophyllotoxin was converted into important intermediate product 4β-isothiocyanate-4-deoxypodophyllotoxin through azide, reduction, addition, and elimination, respectively. Then it reacted with a series of hydrazide compounds to obtain various thiosemicarbazide derivatives, which were finally cyclized to afford a series of 4β-(1, 3, 4-oxadiazole-2-amino)-podophyllotoxin derivatives. Previous studies had shown that when R group of 4β-(1, 3, 4-oxadiazole-2-amino)-podophyllotoxin derivatives was methyl, the biological activity has been more potent than podophyllotoxin against HepG2 and HeLa cell lines. Furthermore, it had also exhibited much lower cytotoxicity toward the normal cell lines L929 and Vero than etoposide, podophyllotoxin and fluorouracil. On this basis, a series of novel compounds with R group of linear chain alkyl or cycloalkanes were designed and synthesized to explore compounds with better antitumor activity, higher selectivity, and lower cytotoxicity. Their cytotoxicity in vitro against six tumor cell lines Du-145, HeLa, A549, K562, K562/adr and HepG2 was evaluated by standard MTT assay. Experimental results showed that compounds 6a, 6b and 6d had significant antitumor activity.
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  • 刊出日期:  2014-02-24

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