4-(N-芳基)胺基-6-长链烷氧基取代蝶啶类化合物的合成及其抗肿瘤活性  

Synthesis and antitumor activities of 4-(N-aryl) amino-6-long chain alkoxy pteridine derivatives

作　　者：林锦 王旭 王艰[1] 许秀枝[1] 陈垚昊 李柱来[1] LIN Jin;WANG Xu;WANG Jian;XU Xiuzhi;CHEN Yaohao;LI Zhulai(Department of Medical Chemistry,School of Pharmacy,Fujian Medical University,Fuzhou 350122;Fuzhou Foreign Language School,Fuzhou 350007,China)

机构地区：[1]福建医科大学药学院药物化学系,福州350122 [2]福州外国语学校,福州350007

出　　处：《中国药科大学学报》2018年第1期64-71,共8页Journal of China Pharmaceutical University

基　　金：福建省科技创新联合资金资助项目(No.2016Y9052);福建省高校杰出青年科研人才培育计划资助项目(No.2017B021)~~

摘　　要：采用具有喹唑啉为母核的抗肿瘤药物作为先导化合物,利用生物电子等排原理,设计并合成一系列4-(N-芳基)胺基-6-长链烷氧基取代蝶啶类化合物7a^7l,并利用MTT法测试其对A549、KG1a和HGC-27肿瘤细胞的增殖抑制作用。以3-氨基吡嗪-2-羧酸甲酯为起始底物,通过6步反应合成12种目标化合物(7a^7l)并确证其结构(~1H NMR、^(13)C NMR、MS)。生物活性试验表明,蝶啶4位为2-氯-5-硝基苯胺基取代时,其活性均高于其他苯胺基取代的产物。化合物7b对A549的活性(IC_(50)=11.55μmol/L)与阳性对照物吉非替尼(IC_(50)=5.95μmol/L)十分接近;化合物7k对3组细胞的IC_(50)均十分接近对照物吉非替尼。由于筛选出的化合物均有2-氯-5-硝基苯胺基片段,可以此结构为基础进行深入研究。A series of4-(N-aryl)amino-6-alkoxyl pteridine derivatives was designed and synthesized via the bioisostere principle using anti-cancer drugs with quinazoline cores as lead compounds.The proliferative inhibitory activities of the synthesized compounds against tumor cells A549,KG1a and HGC-27were also performed by MTT assay.Using methyl3-aminopyrazine-2-carboxylate as the starting material,12target compounds(7a-7l)were synthesized through six-step reaction,and characterized by1H NMR,13C NMR and MS.It was showed that antitumor activity of pteridines with2-chloro-5-nitro-anilino substituted in position4was more potent than that of others.The activity of compound7b on A549cells(IC50=11.55μmol/L)was closely approximate to that of positive control gefitinib(IC50=5.95μmol/L).IC50values of compound7k on three cell lines were all close to those of gefitinib.A2-chloro-5-nitro-anilino fragment was contained in preferred compounds which might be modified for further investigation.

关 键 词：蝶啶 喹唑啉 合成 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学] R965[医药卫生—药学]