2-取代-3-氧代羊毛甾烷-24-酰胺类化合物的合成及抗肿瘤活性研究  

The synthesis and antiproliferative effects of 2-substituted-3-oxo-lanostane-24-oic acid amide derivatives in tumor cells

作　　者：张娜[1] 李坤[1] 庞聪[1] 刘丹[1] 赵临襄[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2015年第4期247-254,共8页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(81273360)

摘　　要：目的设计合成一系列2-取代-3-氧代羊毛甾烷-24-酰胺类化合物,并考察其体外抗肿瘤活性。方法以羊毛甾醇为起始化合物,对其A环和侧链24位双键进行结构改造,经多步反应合成目标化合物。以阿霉素为阳性对照药,采用MTT法测试目标化合物对PC-3和As PC-1细胞的生长抑制活性。结果与结论设计并合成了18个羊毛甾醇衍生物,结构均经1H-NMR、MS、IR谱确证。药理试验结果表明,目标化合物的抗肿瘤活性较羊毛甾醇均有所提高,其中化合物9b、9g、9h、10d、10f、10g对PC-3细胞表现出显著的生长抑制活性,IC50值小于3μmol·L-1;化合物9d、9e、9f、10d对As PC-1细胞表现出显著的生长抑制活性,IC50值小于3μmol·L-1;化合物10d对PC-3和As PC-1细胞的生长抑制活性与阳性对照药阿霉素相当。初步构效关系研究表明,A环2位氰基取代优于碘代,侧链24位引入哌啶基哌啶、N-甲基哌嗪、3,5-二甲基哌啶活性较好。A novel series of 2-substituted-3-oxo-lanostane-24-oic acid amide derivatives were designed and synthesized to investigate their antitumor activity in vitro. Eighteen target compounds were obtained through modifying the natural product lanosterol, whose chemical structures were confirmed by the application of MS, IR, H-NMR. The antiproliferative effects of the target compounds against PC-3 and AsPC-1 were eva- luated by MTT assays with doxorubicin as a positive control. The majority of these derivatives showed pre- ferable growth inhibitory activity than lanosterol. Among which, compounds 9b, 9g, 9h, 10d, 10f and 10g displayed significant growth inhibitory activity against PC-3 cells; compounds 9d,9e,9f and 10d possessed robust growth inhibitory activity against AsPC-1 cells. Of note is that compound 10d exhibited comparable inhibitory activity against PC-3 and AsPC-1 cells with doxorubicin, which was worthy of further investigation. Structure-activity relationships revealed that the introduction of 2-cyano is better than 2-1 in ring A and the amide derivatives were more potent than lanosterol, compounds bearing 4-piperidyl piperidine, N-methyl piperazine and 3,5-dimethyl piperidine were the most potent.

关 键 词：羊毛甾醇 结构修饰 抗肿瘤活性 构效关系 

分 类 号：R914[医药卫生—药物化学]