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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 novel 17-substituted estradiol-pyrimidine derivatives and study their anti-tumor activity in vitro. Methods: Estradiol was used as the raw material and triphenylmethyl chloride was used to protect the hydroxyl group at the 3-position. The product was reacted with dibromoalkane by Williamson method. Then the triphenylmethane protecting group was removed by CH3COOH under “one-pot” Finally, with the reaction of uracil or thymine, 12 novel 17-substituted estradiol-pyrimidine derivatives were synthesized and their structures were characterized. Anti-tumor activity was tested by MTT method. Results: Compounds 11, 13 and 15 showed good proliferation inhibitory activity (> 60%) against MCF-7, while none of dimeric compounds (6,8,10,12,14,16) Showed significant proliferation inhibitory activity (<19%). Compounds 13 and 15 showed the best inhibitory activity on MDA-MB-231 (about 34%). Most of the compounds showed no obvious proliferation inhibitory activity on SKOV-3, NCI-H460 and MGC-803. CONCLUSION: The 17-substituted estradiol-pyrimidine derivatives have better inhibitory activity on MCF-7 than other tumor cells (MDA-MB-231, SKOV-3, NCI-H460 and MGC-803). Thymine derivatives have a broader spectrum of anti-tumor cell proliferative activity than uracil derivatives.