呫吨酮并吡啶季铵盐的合成及其生物活性  

Synthesis and Bioactivity of Quaternary Ammonium Salts of Xanthono-pyridine

作　　者：覃江克[1] 兰文丽[1] 韩留玉[1] 唐煌[1] 苏桂发[1] 戴支凯[2] 徐庆[2] 

机构地区：[1]广西师范大学化学化工学院,药用资源化学与药物分子工程教育部重点实验室,桂林541004 [2]桂林医学院药理实验中心

出　　处：《应用化学》2010年第5期528-532,共5页Chinese Journal of Applied Chemistry

基　　金：广西科技开发计划应用基础研究专项(桂科基0639030;0731054);广西师大科研基金资助项目

摘　　要：以邻碘苯甲酸和8-羟基喹啉为原料,通过Ullmann反应合成了呫吨酮并吡啶(2),再将其进行季铵化反应合成了它的甲基及乙基季铵盐化合物3a和3b,用IR、NMR、MS及元素分析等测试技术对其结构进行了表征。运用四甲基偶氮唑盐微量酸反应比色法(MTT法)测得化合物3a和3b对体外培养人卵巢癌(A2780)、宫颈癌(Hela)、肺癌(SPC-A)和口腔上皮癌(KB)细胞的抑制作用均优于阳性对照药5-氟尿嘧啶(5-Fu)。溴乙锭置换荧光探针法测得化合物3a和3b与小牛胸腺DNA(CT-DNA)的表观结合常数分别为3.91×105和2.72×105L/mol,揭示目标化合物的抗癌活性可能与其跟DNA的相互作用有关。化合物3a和3b对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)均具有良好的选择性抑制活性,IC50值达μmol/L以下,与阳性对照药氢溴酸加兰他敏(Galantamine.HBr)近似,它们对AChE的抑制作用为非竞争性抑制。Xanthono-pyridine（2） was synthesized by means of Ullmann method from o-iodobenzoic acid and 8-hydroxyquinoline;then compound 2 was treated with methyl iodide,ethyl iodide to afford quaternary ammonium salts 3a and 3b,respectively.Their structures were confirmed by IR,NMR,MS and elemental analysis.The two target compounds＇ cytotoxic activities against four human cancer cell lines including A2780（ovarian cancer）,Hela（cervical cancer）,SPC-A（liver cancer） and KB（oral epithelial carcinoma）,were evaluated in vitro by MTT method,the results show that the activities of both salts 3a and 3b were better than that of the positive control 5-Fu.Ethidium bromide displacement assay showed that the apparent binding constants（K_app） of compound 3a and 3b with CT-DNA（calf thymus） were 3.91×105 L/mol and 2.72×105 L/mol,respectively,which suggests that their anti-cancer capabilities might be associated with their interactions with DNA.Their inhibitory activities on acetylcholinesterase（AChE） and butyrylcholinersterase（BuChE） were studied as well.The two compounds showed better and almost equivalent inhibitory activity on AChE.The IC_50 values reach μmol/L level,which are close to that of Galantamine·HBr;enzyme kinetic study indicates that the type of their inhibition on AChE was non-competitive action.

关 键 词：呫吨酮并吡啶 季铵盐 合成 胆碱酯酶 抗癌 DNA 

分 类 号：O625[理学—有机化学]