4(3H)-喹唑啉酮芳胺衍生物的合成及其抗肿瘤活性评价  

Synthesis and Evaluation of 4(3H)-Quinazolinone Derivatives Bearing Aromatic Amine Side Chains as Antitumor Agents

作　　者：曹胜利[1] 冯玉萍[2] 张玫[1] 蒋宇扬[2,3] 宇小青[3] 莫卓华[3] 

机构地区：[1]首都师范大学化学系,北京100037 [2]清华大学化学系,教育部生命有机磷化学与化学生物学重点实验室 [3]清华大学深圳研究生院,广东省化学生物学重点实验室,深圳

出　　处：《应用化学》2007年第2期162-167,共6页Chinese Journal of Applied Chemistry

基　　金：北京市自然科学基金(7042006);北京市优秀人才培养专项经费(20041D0501601)资助项目

摘　　要：根据非经典抗叶酸剂的结构特点,将抗肿瘤药效团三甲氧基苯基与4(3H)-喹唑啉酮结构相结合,设计了一系列具有芳胺侧链的4(3H)-喹唑啉酮衍生物。使用适量的卤代烷,在室温下对3．4,5-三甲氧基苯胺进行N-烷基化反应,制得了4种N-取代的3,4,5-三甲氧基苯胺,收率为30．3％～60．6％。将2-甲基-6-溴甲基-4(3H)-喹唑啉酮与3,4,5-三甲氧基苯胺、N-取代的3,4．5-三甲氧基苯胺以及其它芳胺在室温下反应,以30．8％～71．9％的收率合成了目标化合物8a～8m,其结构用ESI-MS、~1H NMR、元素分析或HRMS测试技术进行了表征。采用MTF法测试了化合物8a～8m对人非小细胞肺癌A-549、结肠癌HCT-8和肝癌Bel-7402细胞的体外抗肿瘤活性。结果表明,在5×10^(-6)g/mL质量浓度下所合成的化合物对3种肿瘤细胞的体外生长的抑制率均低于25％。Based on the structural feature of nonclassical antifolates, a series of 4（3H）-quinazolinone derivatives bearing aromatic amine side chains have been designed by incorporating trimethoxyphenyl, an antitumor pharmacophore, with 4（3H）-quinazolinone. N-alkylation of 3,4,5-trimethoxyphenylamine with appropriate amount of alkyl halides afforded 4 kinds of N-substituted 3,4,5-trimethoxyphenylamines in 30. 3% -60. 6% yields. The target compounds 8a- 8m were obtained through the reactions of 6-bromo-2-methyl-4 （3H）-quinazolinone with 3,4,5-trimethoxyphenylamine, N-substituted 3,4,5-trimethoxyphenylamines or other arylamines at room temperature in 30. 8% -71.9% yields, and their structures were confirmed by means of ESIMS, ^1H NMR, elemental analysis or HRMS. The in vitro cytotoxicities against A-549（ human non-small cell lung cancer）, HCT-8（ human colon cancer） and Bel-7402（ human liver cancer） cell lines of the synthesized compounds 8a -8m were tested with colorimetric MTT assay, and the results indicated that the percent growth inhibition against A-549, HCT-8 and Bel-7402 cell lines at 5 × 10^ -6 g/mL concentration of the compounds 8a -8m were all lower than 25%.

关 键 词：4(3H)-喹唑啉酮衍生物 合成 抗肿瘤活性 MTT试验 

分 类 号：O621.3[理学—有机化学]