DROLOXIFENE枸橼酸盐的工艺改进及其新的生物活性  

SYNTHESIS OF DROLOXIFENE CITRATE AND ITS NEW BIOACTIVITY

作　　者：陈瑛[1] 夏鹏[1] 张倩 郑云红[1] 夏奕[2] 杨征宇 

机构地区：[1]上海医科大学药学院有机化学教研室,上海 200032 [2]Natural Products Laboratory Division of Medical Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill ,North Carolina 27599-7360,USA

出　　处：《药学学报》2000年第12期902-905,共4页Acta Pharmaceutica Sinica

基　　金：上海市科委现代生物与新药产业发展基金资助(955419002);国家科委生命技术发展中心医药技术创新博士项目资助(217010)

摘　　要：目的　探索droloxifene的合成方法 ,并对其新的生物活性进行研究。方法和结果　以甲氧基苯和苯乙酸为原料 ,经酰氯化、付 克反应、烷基化、去甲基化、醚化、格氏加成、消除脱水、构型转化及成盐共 9步反应 ,得droloxifene枸橼酸盐 ,8步收率 14 7% (9 2 % [1] )。生物活性实验发现其具有缓解肿瘤细胞多药耐药性和诱导黄体细胞凋亡的两种新的生物活性。结论　本文对droloxifene的合成工艺进行了改进 ,反应步骤缩短两步 ,异构体分离、转化方法简便 ,原料及试剂易得 ,操作简便。两种新的生物活性的发现对新药研究及扩大临床应用提供了实验依据。AIM To investigate a feasible synthetic procedure of droloxifene and study on its new bioactivities. METHODS AND RESULTS Droloxifene was synthesized using methoxybenzene and phenylacetic acid as starting materials, via Friedel Crafts acylation, alkylation, demethylation, etherification, Grignard addition, elimination dehydration, conversing configuration and forming citrate, totally 8 steps, overall yield 14 7% (9 2% [1] ). By pharmacological test, droloxifene citrate shows two new bioactivities: (1) obvious effect on reversing the MDR of K562/A02 cells and modulating mdrl, GSTπ and TopoIIα expression. (2) inducing apoptosis in cultured rat luteal cell. CONCLUSION The improved synthetic procedure is shorter than the reported method by two steps and has advantages of simple separation, purification and conversion of configuration; easily available starting materials and reagents; concise operation. Two new bioactivities on reversing MDR and inducing apoptosis of luteal cell offered a clue in new drugs research and widened clinic application of droloxifene.

关 键 词：DROLOXIFENE 枸橼酸盐 抗癌药 生物活性 

分 类 号：TQ463.4[化学工程—制药化工]