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

新型环磷酰胺前药:环磷酰胺哌嗪季铵盐的构效关系(英文)

作　　者：杨青[1] 朱继让 孙崎[1] 崔景荣[1] 李润涛[1] 葛泽梅[1] 

机构地区：[1]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

出　　处：《Journal of Chinese Pharmaceutical Sciences》2010年第1期24-33,共10页中国药学（英文版）

基　　金：Foundation items:National Nature Science Foundation of China (Grant No. 20472008);the Major State Basic Research Development Program (Grant No. 2004CB719900)

摘　　要：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 （H 22）.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.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：Cyclophosphamide piperaziniums Prodrug Anticancer activity Synthesis DNA-binding 

分 类 号：R914[医药卫生—药物化学]