新型环磷酰胺前药: 环磷酰胺哌嗪季铵盐的构效关系

新型环磷酰胺前药: 环磷酰胺哌嗪季铵盐的构效关系

杨青, 朱继让, 孙崎^*, 崔景荣, 李润涛, 葛泽梅^*

北京大学天然药物及仿生药物国家重点实验室; 药学院化学生物学系, 北京 100191

收稿日期:2009-09-03 修回日期:2009-11-15 出版日期:2010-01-15 发布日期:2010-01-15
通讯作者: 孙崎*, 葛泽梅*

A novel class of cyclophosphamide prodrug: structure-activity relationships of cyclophosphamide piperaziniums

Qing Yang, Ji-Rang Zhu, Qi Sun^*, Jing-Rong Cui, Run-Tao Li, Ze-Mei Ge^*

State Key Laboratory of Natural and Biomimetic Drugs; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

Received:2009-09-03 Revised:2009-11-15 Online:2010-01-15 Published:2010-01-15
Contact: Qi Sun*, Ze-Mei Ge*

摘要/Abstract

摘要： 作为对环磷酰胺结构改造新思路的延续, 本文以化合物9i为先导物设计并合成了三个系列环磷酰胺哌嗪季铵盐类衍生物(10, 11和13)。通过体内抗肿瘤活性试验, 其构效关系表明: 1) 环磷酰胺螺环哌嗪季铵盐(10)的构象和N-3位的取代基对活性影响极大; 2) 不同类型的环磷酰胺非螺环哌嗪季铵盐(11)显示出其抗肿瘤活性的差异; 3) 选择合适的季铵盐部分, 化合物1,2-苯并异恶唑磷酰哌嗪季铵盐(13)有可能具有抗肿瘤活性。此研究结果将有助于进一步设计和改造各种氮芥类抗肿瘤药物。

关键词: 环磷酰胺哌嗪季铵盐, 前药, 抗肿瘤活性, 合成, DNA-链接

Abstract: A new strategy for the modification of cyclophosphamide was carried out and three series of new cyclophosphamide piperazinium salts 10, 11 and 13 were prepared. These compounds, based on compound 9i scaffold, were evaluated for their in vivo anticancer activities against hepatocyte sarcoma 22 (H22). The structure-activity relationship study reveals that 1) the conformation and the substituent at N-3 of cyclophosphamide spiropiperazinium salts 10 greatly affect the activity; 2) different kinds of cyclophosphamide non-spiropiperazinium derivatives 11 show different activities; 3) for 1,2-benzisoxazole phosphoropiperazinium salts 13, it is possible to obtain anticancer drug candidates with suitable quaternary ammonium moiety. These results would help to further design and synthesize analogs of mustard anticancer drugs.

Key words: Cyclophosphamide piperaziniums, Prodrug, Anticancer activity, Synthesis, DNA-binding

中图分类号:

R916.41

Supporting: Foundation items: National Nature Science Foundation of China (Grant No. 20472008) and the Major State Basic Research Development Program (Grant No. 2004CB719900).
^*Corresponding author. Tel.: 86-10-82801504; fax: 86-10-82716956

杨青, 朱继让, 孙崎^*, 崔景荣, 李润涛, 葛泽梅^*. 新型环磷酰胺前药: 环磷酰胺哌嗪季铵盐的构效关系[J]. .

Qing Yang, Ji-Rang Zhu, Qi Sun^*, Jing-Rong Cui, Run-Tao Li, Ze-Mei Ge^* . A novel class of cyclophosphamide prodrug: structure-activity relationships of cyclophosphamide piperaziniums [J]. .

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