17-取代雌二醇-嘧啶类衍生物的合成与体外抗肿瘤活性研究  

Synthesis and in vitro anti-tumor activities of17-substituted estradiol-pyrimidine derivatives

作　　者：程克光[1] 张江玉 刘观艳[1] 初相伍[1] 凌丹[1] 姚国义[1] 

机构地区：[1]广西壮族自治区药用资源化学与药物分子工程重点实验室广西师范大学化学与药学学院,桂林541004

出　　处：《中国新药杂志》2014年第2期219-225,共7页Chinese Journal of New Drugs

基　　金：国家“973”计划前期研究专项(2011CB512005);广西教育厅科研项目(201202ZD008);教育部重点实验室“药用资源化学与药物分子工程”课题(CMEMR 2012-B03,CMEMR 2013-A01)

摘　　要：目的:合成新型17-取代雌二醇-嘧啶类衍生物,并研究其体外抗肿瘤活性。方法:以雌二醇为原料,三苯基氯甲烷保护3位羟基;经Williamson合成法,与二溴烷烃反应;继而在"一锅煮"条件下,用CH3COOH脱除三苯基甲烷保护基;最后与尿嘧啶或胸腺嘧啶反应,共合成得到12个新型的17-取代雌二醇-嘧啶类衍生物,并对其结构进行表征。采用MTT法测试抗肿瘤活性。结果:化合物11,13和15对MCF-7表现出很好的增殖抑制活性(>60%),而二聚体化合物(6,8,10,12,14,16)对MCF-7均未显示明显的增殖抑制活性(<19%)。化合物13和15对MDA-MB-231的增殖抑制活性最好(约34%)。大部分化合物对SKOV-3,NCI-H460和MGC-803均未显示明显的增殖抑制活性。结论:合成得到的17-取代雌二醇-嘧啶类衍生物对MCF-7的增殖抑制活性优于其他肿瘤细胞(MDA-MB-231,SKOV-3,NCI-H460和MGC-803)。胸腺嘧啶衍生物比尿嘧啶衍生物具有更广谱的抗肿瘤细胞增殖活性。Objective：To synthesize 17-substituted estradiol-pyrimidine derivatives and evaluate their in vitro anti-tumor activities.Methods：Estradiol was reacted with triphenylmethylchloride to protect the 3-hydroxyl group.Subsequently,the triphenylmenthyl derivative was reacted with dibromo alkane through Williamson synthesis,followed by deprotection of triphenylmethyl group through CH 3 COOH in＂one-pot＂.Finally,the ω-bromoalkyl estradiol derivative was reacted with uracil or thymine,to generate corresponding target 17-substituted estradiol-pyrimidine derivatives.MTT assay was used to test anti-tumor activity of synthesized compounds against human tumor cell lines.Results：Compounds 11,13 and 15 exhibited excellent inhibitory activity against proliferation of MCF-7 cells（＆gt; 60%）,while the dimer compounds（6,8,10,12,14 and 16） showed poor activity（＆lt; 19%）.Compounds 13 and 15 showed better inhibitory activity against proliferation of MDA-MB-231 cells（~ 34%） than other compounds.Most of synthesized compounds did not show remarkable inhibitory activities against proliferation of SKOV-3,NCI-H460 and MGC-803 cells.Conclusion：The synthesized 17-substituted estradiol-pyrimidine derivatives have better inhibitory activities against proliferation of MCF-7 than other tested tumor cells（MDA-MB-231,SKOV-3,NCI-H460 and MGC-803 cells）.Thymidine derivatives possess a broader spectrum of anti-tumor cell proliferation than that of uracil derivatives.

关 键 词：17-取代雌二醇 尿嘧啶 胸腺嘧啶 合成 抗肿瘤 

分 类 号：R914.5[医药卫生—药物化学]