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

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.