2,4-二氨基嘧啶类FAK抑制剂的设计合成及活性评价  

Design,synthesis and biological evaluation of 2,4⁃diaminopyrimidines FAK inhibitors

作　　者：王鑫[1] 秦桥花 付清林 郭志强 卢书雨 于思佳 赵冬梅[1] WANG Xin;QIN Qiao-hua;FU Qing-lin;GUO Zhi-qiang;LU Shu-yu;YU Si-jia;ZHAO Dong-mei(Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016

出　　处：《中国药物化学杂志》2023年第7期498-507,共10页Chinese Journal of Medicinal Chemistry

摘　　要：目的 设计合成一系列2,4-二氨基嘧啶类衍生物,以期得到对黏着斑激酶(FAK)具有较好抑制活性的新化合物。方法 以邻硝基苯甲酸为原料,经酰化、缩合、催化氢化得到中间体N-甲基-2-氨基苯甲酰胺(4)。以邻氟硝基苯为原料,经取代、氧化、催化氢化得到中间体2-(异丙基磺酰基)-苯胺(7)。以对氟硝基苯为原料,经取代、催化氢化得到4-(4-氨基苯基)哌嗪-1-羧酸叔丁酯(10)。以2,4,5-三取代嘧啶为原料,先与不同的苯胺(4或7)在4位发生取代,然后与10在2位发生取代,再经脱Boc保护,最后与二硫化碳以及不同取代的卤代烃先加成后取代得到目标化合物(15a~15o),并对目标化合物进行体外酶活性测试。结果与结论设计并合成了新型2,4-二氨基嘧啶类化合物15个,所有化合物均未见文献报道,其结构均经1H-NMR和MS确证,部分化合物结构经13C-NMR和HR-MS确证。其中化合物15d对FAK的抑制活性(IC50=15.8 nmol·L^(-1))与阳性对照化合物TAE-226相当。Fifteen 2,4⁃diaminopyrimidine derivatives as FAK inhibitors were designed and synthesized.The target compounds were synthesized by acylation,condensation,catalytic hydrogenation,substitution,oxidation,addition and other reactions,and these compounds were confirmed by 1H⁃NMR and MS,some compounds were confirmed by 13C⁃NMR and HR⁃MS.The enzyme inhibitory activities of target compounds were tested using HTRF assay.The results showed that 2⁃hydroxyethyl 4⁃(4⁃((5⁃chloro⁃4⁃((2⁃(methyl⁃carbamoyl)phenyl)amino)pyrimidin⁃2⁃yl)amino)phenyl)piperazine⁃1⁃carbodithioate(15d)displayed best inhibitory activity against FAK with an IC50 value of 15.8 nmol·L^(-1),which was comparable with positive compound TAE⁃226.

关 键 词：FAK抑制剂 2 4-二氨基嘧啶类化合物 抗肿瘤 合成 

分 类 号：R914[医药卫生—药物化学]