3-取代雌二醇-嘧啶类衍生物的合成与抗肿瘤活性

以雌二醇为原料，在K₂CO₃碱性条件下，与二溴烷烃反应生成醚类化合物，继而与尿嘧啶或胸腺嘧啶反应，共合成16个新型3-取代雌二醇-嘧啶类衍生物(化合物5~20)，并采用MTT法对其进行抗肿瘤活性测试。结果表明，这些化合物对人乳腺癌MCF-7和MDA-MB-231、人卵巢癌SKOV-3、人肺癌NCI-H460和人胃癌MGC-803细胞株表现出不同程度的抑制活性。其中，连接链长为2的尿嘧啶单接产物5和双接产物6、连接链长为8的尿嘧啶单接产物17、连接链长为2和6的胸腺嘧啶双接产物8和16对MCF-7具有良好的增殖抑制活性；化合物5和6对MDA-MB-231细胞株具有较好的增殖抑制活性；化合物17同时对SKOV-3细胞株也呈现优良的增殖抑制活性。连接链长为6的尿嘧啶单接产物13对MGC-803细胞株的增殖抑制率最高。总之，3-取代的雌二醇-嘧啶类衍生物对MCF-7细胞株的增殖抑制活性要优于其他受试肿瘤细胞株。3-取代雌二醇-尿嘧啶衍生物比3-取代雌二醇-胸腺嘧啶衍生物具有更好的抗肿瘤细胞增殖活性。

Synthesis and antitumor activities of 3-substituted estradiol-pyrimidine derivatives

3-Substituted estradiol-pyrimidine derivatives were synthesized starting from estradiol. Estradiol was reacted with dibromo alkane in the presence of K₂CO₃ to give the corresponding ethers, which were reacted with uracil or thymine, to afford sixteen target compounds. MTT assay was used to evaluate the antitumor activity of the target compounds against human cancer cell lines. The results showed that the target compounds exhibited varying degrees of inhibitory activity against the tumor cell lines. Compounds 5(the connecting chain length of 2, single-access uracil product), 6(the connecting chain length of 2, dual access uracil product), 17(the connecting chain length of 8, single-access uracil product), 8(the connecting chain length of 2, dual-access thymine product)and 16(the connecting chain length of 6, dual-access thymine product)showed excellent proliferation inhibiting activity against tumor cell lines MCF-7. Compounds 5 and 6 also exhibited good proliferation inhibiting activity against MDA-MB-231. Compound 17 also possessed good proliferation inhibiting activity against SKOV-3. Compound 13, with the connecting chain length of 6, uracil single-access product, exhibited the most potent inhibition of proliferation against MGC-803. Overall, 3-substituted estradiol-pyrimidine derivatives exhibited better proliferation inhibiting activity against MCF-7 than other tested tumor cells(MDA-MB-231, SKOV-3, NCI-H460 and MGC-803). 3-Substituted estradiol-uracil derivatives possessed better anti-proliferative activity of tumor cells than 3-substituted estradiol-thymidine derivatives.