(E)-N-取代亚甲基-3-[4-(吡啶-4-基)嘧啶-2-基]氨基苯甲酰肼衍生物的设计、合成及抗结肠癌活性研究  

Design,Synthesis and Anti-Colon Cancer Activity of Evaluation(E)-N-Substituted Methylene-3-[4-(pyridin-4-yl)pyrimidin-2-yl]Amino Benzoylhydrazide Derivatives

作　　者：彭琴玮 盛含晶 何凤明 赵俊明 邵玲莉[3] 章昭琳 胡鸿雨[1] PENG qinwei;SHENG hanjing;HE Fengming;ZHAO Junming;SHAO Lingli;ZHANG Zhaolin;HU Hongyu(Xingzhi College,Zhejiang Normal University,Lanxi 321100,China;School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,China;Jinhua Polytechnic,Jinhua 321007,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]金华职业技术学院,浙江金华321007

出　　处：《中国药学杂志》2023年第23期2145-2156,共12页Chinese Pharmaceutical Journal

基　　金：浙江省公益基金项目资助(LGF22H300015);金华市公益性技术应用研究项目资助(2022-4-031,2022-4-004);国家级大学生创新创业训练计划项目资助(202113276001,202113276009)。

摘　　要：目的设计合成(E)-N-取代亚甲基-3-[4-(吡啶-4-基)嘧啶-2-基]氨基苯甲酰肼衍生物,并对其抗癌的活性进行研究。方法3-氨基苯甲酸乙酯为起始原料,通过4步反应合成了一系列目标化合物7a~7p,并通过^(1)H-NMR、^(13)C-NMR和HRMS对所有目标化合物进行了结构鉴定。采用MTT法、免疫印迹法、细胞侵袭实验、损伤愈合实验和EdU染色试剂检测了合成化合物对于结肠癌细胞生长的抑制作用。结果目标化合物对于结肠癌细胞的生长具有一定的抑制活性,其中化合物7m活性最优,其抑制结肠癌细胞系HT-29和RKO的IC50值分别为(1.04±0.16)和(1.54±0.20)μmol·L^(-1),且7m对正常结肠上皮细胞的毒性较小(IC_(50)>100μmol·L^(-1))。此外,7m能与Nur77结合,并以浓度依赖的方式抑制结肠癌细胞中Nur77和p-mTOR蛋白的表达。进一步研究表明化合物7m能以Nur77依赖的方式抑制结肠癌细胞的EMT进程。结论该系列化合物具有较好的抗结肠癌的活性,具有进一步研究的意义。OBJECTIVE To design and synthesize(E)-N-substituted methylene-3-[4-(pyridin-4-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 7a-7p 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.The inhibitory effects of the synthesized compounds on colon cancer cells were examined by MTT assay,immunoblotting,cell invasion assay,wound-healing assay,and EdU staining assay.RESULTS The target compounds showed inhibitory activity against the growth of colon cancer cells,of which compound 7m had the highest activity with IC_(50) values of(1.04±0.16)and(1.54±0.20)μmol·L^(-1) against HT-29 and RKO cell lines,respectively,and it was less toxic to normal colon.Furthermore,7m could bind to Nur77 and inhibited the expression of Nur77 and p-mTOR proteins in colon cancer cells in a concentration-dependent manner.Further studies showed that compound 7m could inhibit the EMT process in colon cancer cells in a Nur77-dependent manner.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 结肠癌 上皮间质转化 细胞增殖 孤儿核受体 磷酸化雷帕霉素靶蛋白 

分 类 号：R914[医药卫生—药物化学]