1,2,3-三氮唑并[4,5-d]嘧啶酮三环类衍生物的合成及抗肿瘤活性研究  

Synthesis and antitumor activity of novel tricyclic-[1,2,3] triazolo[4,5-d] pyrimidone derivatives

作　　者：刘奇 聂礼飞[1] BOZOROV Khurshed 赵江瑜[1] LIU Qi;NIE Li-fei;BOZOROV Khurshed;ZHAO Jiang-yu(State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization,Xinjiang Technical Institute of Physics and Chemistry,Chinese Academy of Sciences,Urumqi,Xinjiang 830011,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]中国科学院,新疆理化技术研究所,新疆特有药用资源利用省部共建重点实验室培育基地,新疆乌鲁木齐830011 [2]中国科学院大学,北京100049

出　　处：《中国药物化学杂志》2021年第12期945-954,共10页Chinese Journal of Medicinal Chemistry

基　　金：国家基础科学公共科学数据中心资助项目(NBSDC-DB-19)。

摘　　要：目的设计合成天然产物deoxyvasicinone和mackinazolinone类似物1,2,3-三氮唑并[4,5-d]嘧啶酮三环系列化合物,以期发现具有抗肿瘤活性的化合物。方法采用商业易得的苯胺为起始原料,通过重氮化、[3+2]环加成、催化环化等步骤合成了27个结构新颖的三环类化合物;采用MTT法(以阿霉素作为阳性对照物),对宫颈癌(HeLa)、人结肠癌(HT-29)和乳腺癌(MCF-7)3种肿瘤细胞进行了体外抗肿瘤活性研究。结果体外活性筛选结果表明,部分化合物对HeLa细胞具有一定的抑制作用,其中化合物5i抑制活性最佳,其IC_(50)值为17.90±0.99μmol·L^(-1),化合物5e对HT-29细胞也表现出一定的增殖抑制活性,其IC_(50)值为43.58±2.91μmol·L^(-1)。结论初步构效关系研究表明,三环体系中脂肪氮杂环为六元环(n=2)时活性较七元环(n=3)和五元环(n=1)好,且当苯环上含有氯原子、溴原子时,有利于提高化合物的体外抗肿瘤活性。Deoxyvasicinone and mackinazolinone,which belong to the typical natural alkaloids,were usually used as the core of drug structure in many research,but their scaffold lack reconstruction.To find the compounds with higher antitumor activity,27 novel tricyclic-[1,2,3]-triazolo[4,5-d]pyrimidone derivatives have been designed and synthesized,which are the analogues of natural compounds deoxyvasicinone and mackinazolinone.Target derivatives were synthesized from some readily avalible aniline compounds by azidation,[3+2] cycloaddition and POCl_(3)-catalyzed cyclization.Their structures were confirmed by ^(1)H-NMR,^(13)C-NMR and HR-MS.Using doxorubicin as positive control,the antitumor activities against three cancer cells in vitro of the target compounds were evaluated by MTT assay.Among them,some target compounds had potent activity against HeLa cells lines.Compound 5 i showed the best antitumor activity with IC_(50)=17.90±0.99 μmol·L^(-1),and compound 5 e showed moderate antiproliferative activity against human colorectal adenocarcinoma cell line with IC_(50)=43.58±2.91 μmol·L^(-1).■.

关 键 词：1 2 3-三氮唑并[4 5-d]嘧啶酮 抗肿瘤 衍生物 

分 类 号：R914[医药卫生—药物化学]