新型7-甲基-5,6,7,8-四氢-3H-吡啶并[4′,3′∶4,5]噻吩并[2,3-d]嘧啶酮类Schiff碱的合成及抗肿瘤活性研究  

Synthesis and Anti-tumor Activity Evaluation of Novel 7-Methyl-5,6,7,8-tetrahydro-3H-pyrido[4′,3′∶4,5]thieno[2,3-d]pyrimidinone Schiff Bases

作　　者：李吉莹[1] 曾慧君 陈慧琼 韩潇[1] LI Ji-ying;ZENG Hui-jun;CHEN Hui-qiong;HAN Xiao(Changjiang Polytechnic,Wuhan 430074,China;Wuhan Institute for Food and Cosmetic Control,Wuhan 430012,China;Wuhan Aimin Pharmaceutical Limited Company,Ezhou 436070,China)

机构地区：[1]长江职业学院,湖北武汉430074 [2]武汉食品化妆品检验所,湖北武汉430012 [3]武汉爱民制药股份有限公司,湖北鄂州436070

出　　处：《化学试剂》2020年第7期755-760,共6页Chemical Reagents

基　　金：湖北省普通高等学校人文社会科学重点研究基地湖北技能型人才培养研究中心项目(2018JB009);2019年全国食品工业职业教育教学指导委员会教学教改研究课题项目(SH249);湖北省教育厅科研计划项目(B2017578)。

摘　　要：以1-甲基-4-哌啶酮为原料,经过Gewald、成环、缩合等反应合成了14个新型7-甲基-5,6,7,8-四氢-3H-吡啶并[4′,3′∶4,5]噻吩并[2,3-d]嘧啶酮类Schiff碱,其结构经1HNMR和MS进行确证。初步的生物活性结果表明,目标化合物对荷尔蒙依赖型乳腺癌细胞MCF-7和三阴性乳腺癌细胞MDA-MB-231均有抑制活性,半数抑制浓度(IC50)值均达到微摩尔级,其中部分化合物的抗肿瘤活性甚至强于阳性药物5-氟尿嘧啶(5-FU)和他莫昔芬。尤其是3-(二茂铁亚胺基)-7-甲基-5,6,7,8-四氢-3H-吡啶并[4′,3′∶4,5]噻吩并[2,3-d]嘧啶-4-酮对MCF-7和MDA-MB-231这两种乳腺癌细胞均展现出了最强的抑制活性,其IC50分别为10.5、7.1μmol/L;此外,目标化合物对正常的MCF-10A细胞没有毒性,而5-氟尿嘧啶和他莫昔芬有毒性。Fourteen novel 7-methyl-5,6,7,8-tetrahydro-3H-pyrido[4′,3′∶4,5]thieno[2,3-d]pyrimidinone Schiff bases were designed and synthesized via Gewald,cyclization,condensation reactions using 1-methyl-4-piperidone as the raw material.The structures of these compounds were confirmed by 1HNMR and MS.The anti-tumor activities were evaluated against hormone-dependent breast cancer MCF-7 and triple-negative breast cancer MDA-MB-231 cell lines in vitro.The preliminary biological results showed that these compounds had inhibitory activities against both MCF-7 and MDA-MB-231 with micromolar value of the half maximal inhibitory concentration(IC50),and some of them exhibited activities better than the positive drugs 5-fluorouracil(5-FU)and tamoxifen.Specifically,3-(ferrocenyl)-7-methyl-5,6,7,8-tetrahydro-3H-pyrido[4′,3′∶4,5]thieno[2,3-d]pyrimidin-4-one showed the greatest potency against both MCF-7 and MDA-MB-231,and its IC50 was 10.5,7.1μmol/L,respectively.Additionally,all compounds were nontoxic to health MCF-10 A cells,while 5-FU and tamoxifen showed essential toxicity.

关 键 词：Gewald反应 氮杂-Wittig反应 四氢-3H-吡啶并[4′ 3′∶4 5]噻吩并[2 3-d]嘧啶酮 SCHIFF碱 合成 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]