一些具有3-羟基-5-烯结构甾体骨架衍生物的合成及其VEGF抑制活性  

Synthesis and VEGF inhibition activities of some steroidal analogues with 3-hydroxy-5-ene moiety

作　　者：张璐[1] 戈梅[2] 朱丽[2] 夏鹏[1] 陈瑛[1] 

机构地区：[1]复旦大学药学院药物化学教研室,上海200032 [2]上海来益生物药物研究开发中心有限责任公司,上海201203

出　　处：《复旦学报（医学版）》2008年第6期897-901,907,共6页Fudan University Journal of Medical Sciences

摘　　要：目的设计合成一系列具有3-羟基-5-烯骨架的五环甾体骨架衍生物,并测试其抑制乳腺癌细胞新血管生成的活性的抑制作用。方法以孕烯醇酮醋酸酯为原料经3条不同合成路线对甾体D环16、17及20位进行一系列结构修饰。结果一共合成了12个化合物,其中新化合物有6个,结构均经核磁共振氢谱、碳谱及质谱确证。结论生物活性检测显示上述结构修饰的化合物对乳腺癌细胞血管内皮生长因子(vascularendothelial growth factor,VEGF)的活性均具有显著的抑制作用,EC50均在1 mmol/L或低于1 mmol/L的水平,其中化合物2a和4b的治疗指数TI值高于阳性对照品2-甲氧基雌二醇(2-Methoxyl Estradiol,2-ME)。Objective Some pentacyclic steroidal analogues with 3-hydroxy-5-ene moiety have been synthesized to evaluate inhibition of VEGF in breast cancer cells. Methods 16-Dehydropregnenolone acetate was used as starting material to proceed several modification on its D-ring via three different synthetic routes. Results Twelve target molecules, including 6 new molecules, have been synthesized. The structures of all target compounds were confirmed by ^1H-NMR, ^13C-NMR and MS. Conclusions All target molecules showed potent in vitro inhibition of VEGF in breast cancer cells with EC50 values of 1 mmol/L or sub-mmol/L level. Among them TI values of compounds 2a and 4b were obviously larger than that of positive control 2-ME.

关 键 词：新血管生成 血管内皮生长因子 抑制剂 甾体 

分 类 号：R914.5[医药卫生—药物化学]