N′-取代-4-{3-(喹啉-6-基)脲基}苯甲酰肼衍生物的合成及活性研究  

Synthesis and Activity of N′-Substitute-4-{3-(Quinoline-6-yl)Urea}Benzoyl Hydrazide Derivatives

作　　者：谢育乐 杨伊静 赵胜贤 胡鸿雨[1] XIE Yule;YANG Yijing;ZHAO Shengxian;HU Hongyu(Xingzhi College,Zhejiang Normal University,Lanxi 321100,China;School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,China;College of Science and Technology,Ningbo University,Cixi 315302,China)

机构地区：[1]浙江师范大学行知学院,浙江兰溪321100 [2]厦门大学药学院,福建厦门361102 [3]宁波大学科学技术学院,浙江慈溪315302

出　　处：《中国药学杂志》2024年第3期227-234,共8页Chinese Pharmaceutical Journal

基　　金：国家级大学生创新创业训练计划项目资助(202113276001);金华市公益性技术应用研究项目资助(2022-4-031);宁波市重点公益性科技计划项目资助(2023S015)。

摘　　要：目的 设计合成N′-取代-4-{3-(喹啉-6-基)脲基}苯甲酰肼衍生物,并对其抗乳腺癌活性进行研究。方法 6-氨基喹啉为起始原料,通过3步反应合成了一系列目标化合物4a~4p,并通过^(1)H NMR、^(13)C NMR和HRMS对所有目标化合物进行了结构确证。采用MTT法检测了合成化合物对于乳腺癌细胞的抑制作用。结果 表明目标化合物对于乳腺癌细胞的生长具有一定的抑制活性,其中化合物4e活性最优,表现出明显的抑制作用,抑制乳腺癌细胞系MCF-7的IC_(50)为(2.30±0.34)μmol·L^(-1),且4e对正常乳腺上皮细胞的毒性较小(IC_(50)>100μmol·L^(-1)),优于阳性药Cisplatin。此外4e能够明显上调孤儿核受体Nur77的蛋白表达水平,并且能够使MCF-7出现S期阻滞。结论 该系列化合物具有较好的抗乳腺癌的活性,有进一步研究的价值。OBJECTIVE To design and synthesize N-substituted methylene-3-(4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzohydrazide derivatives,and evaluate their anticancer activities.METHODS Using 3-aminobenzoic acid ethyl ester as the starting reagent,a series of target compounds 4a-4p were synthesized in a 4-step reaction,and all of the target compounds were structurally characterized by ^(1)H-NMR,^(13)C-NMR and HRMS.MTT assay was used to detect the inhibitory effect of synthetic compounds on breast cancer cells.RESULTS It′s showed that the target compounds had certain inhibitory activity on the growth of breast cancer cells,among which compound 4e was the best one,showing obvious inhibitory effect on breast cancer cells.The IC_(50) value of breast cancer cell line MCF-7 was(2.30±0.34)μmol·L^(-1),and the toxicity of 4e to normal mammary epithelial cells was low(IC_(50)>100μmol·L^(-1)).Thus,4e is better than the positive drug cisplatin.In addition,4e could significantly up-regulate the protein expression level of Nur77 and induce the S-phase arrest of MCF-7.CONCLUSION This series of compounds have good anti-cancer activity and are of interest for further study.

关 键 词：苯甲酰肼衍生物 细胞增殖 乳腺癌细胞 孤儿核受体Nur77 S期阻滞 

分 类 号：R914[医药卫生—药物化学]