新型咪唑酮并吡啶类化合物的合成和体外抗肿瘤活性  

Novel imidazolonepyridine-based compounds:the synthesis method and anti-cancer activities

作　　者：马晓东 方方 乔韬 马慧娟 尤雅 陶强强 关晓静 MA Xiao-dong;FANG Fang;QIAO Tao;MA Hui-juan;YOU Ya;TAO Qiang-qiang;GUAN Xiao-jing(College of Pharmacy,Anhui University of Chinese Traditional Medicine,Hefei 230012,China;Department of Medicinal Chemistry,Anhui Academy of Chinese Traditional Medicine,Hefei 230012,China)

机构地区：[1]安徽中医药大学药学院,合肥230012 [2]安徽省中医药科学院药物化学研究所,合肥230012

出　　处：《中国新药杂志》2018年第20期2417-2425,共9页Chinese Journal of New Drugs

基　　金：安徽省高校优秀青年人才支持计划重点资助项目(gxyq ZD2016129);安徽中医药大学自然科学研究重点资助项目(2017zrzd012)

摘　　要：目的:建立一类咪唑酮并吡啶衍生物的合成方法并初步评价其体外抗肿瘤活性。方法:以4-羟基吡啶为起始原料经双硝基化、羟基氯代、芳族亲核取代反应、单硝基还原、环合、N-甲基化、硝基还原、酰化等反应制备目标分子。采用Kinase-Glo Luminescent Assay、Lance Ultra Assay、磺酰罗丹明B法评价其体外抗肿瘤活性。结果:11个目标分子经1HNMR,13CNMR,MS确证。目标分子对磷脂酰肌醇3-激酶α(phosphatidylinositol 3-kinaseα,PI3Kα)、哺乳动物雷帕霉素靶蛋白(the mammalian target of rapamycin,m TOR)均未呈现出明显的抑制活性; 3,5-2(三氟甲基)苯基脲衍生物(27)对结肠癌细胞株HCT-116、前列腺癌细胞株PC-3呈现出中等强度的抗增殖活性。结论:该类化合物结构骨架新颖,具有进一步结构衍生化空间,可用于新型激酶抑制剂的研究。Objective： To establish the preparative method for a class of imidazolonepyridine-based compounds and evaluate their preliminary in vitro anti-tumor activities. Methods： Introducing 4-hydroxyl pyridine as the starting material that underwent di-nitrification,chloriation,SNAr reaction,mono-reduction of the nitro group,cyclization,N-methylation,reduction of the other nitro functionality and acylation to afford the target compounds. Utilizing Kinase-Glo Luminescent Assay,Lance Ultra Assay and SRB Assay to investigate their in vitro anti-tumor activities. Results： The total of 11 compounds were structurally characterized by1 H NMR,13 C NMR and MS. All of them failed to remarkably inhibit both PI3 Kα and m TOR,and the 3,5-bis（ trifluoromethyl） phenyl urea derivative（ 27） exhibited moderate anti-proliferative activities against HCT-116 and PC-3 cell lines. Conclusion：Given the structural novelty of the disclosed imidazolonepyridine scaffold,it offers a platform for further derivatization to explore novel kinase inhibitors.

关 键 词：咪唑酮并吡啶 合成方法 磷脂酰肌醇3-激酶 哺乳动物雷帕霉素靶蛋白 抗增殖活性 激酶抑制剂 

分 类 号：R963[医药卫生—微生物与生化药学]