摘要
目的 设计、合成含嘌呤骨架的EGFR双突变体抑制剂,并评价其抗肺癌细胞增殖活性。方法 以2,4-二氯-5-硝基嘧啶和相应的胺为起始原料,合成中间体1a^1d;以2-甲氧基-4-氟-5-硝基苯胺为原料,经氨基保护、亲核取代、还原、亲核取代、脱保护基后,与中间体1a^1d进行亲核取代反应,再经还原、亲核加成-消除反应合成目标化合物TM1~TM4。采用MTT法评价目标化合物对3种人非小细胞肺癌细胞(A549、HCC827、H1975)增殖抑制活性;采用ADP-Glo法评价目标化合物抑制EGFRL858R/T790M激酶活性。结果与结论 合成了4个未见文献报道的新化合物,其结构均经1 H-NMR和LC-MS谱确证。体外活性测试结果表明,TM1、TM2、TM4显示出较强的抗H1975和HCC827细胞增殖活性;4个目标化合物对EGFR突变细胞(HCC827和H1975)的抑制活性均强于对EGFR野生型(WT)的细胞(A549);TM1和TM2抑制EGFRL858R/T790M的IC50值分别为2.5、2.0nmol·L^-1,与阳性药AZD9291(3.5nmol·L^-1)相当。以嘌呤为骨架,设计合成的目标化合物对EGFR双突变的细胞有较强的抑制活性;目标物TM1和TM2对EGFRL858R/T790M激酶显示出强的抑制作用。
AZD9291 analogues with purine scaffold were designed and synthesized.Intermediates 1a-1d were synthesized via the reactions of 2,4?dichloro?5?nitropyrimidine with corresponding amines.Then,the target compounds were prepared starting from 2?methoxyl?4?fluoro?5?nitroaniline through amine protection,nucleophilic substitution,reduction,nucleophilic substitution,deprotective group,nucleophilic substitution reaction with intermediates 1a-1d,followed by reduction and nucleophilic addition?elimination.The structures of the target compounds were characterized by MS,1H?NMR.Moreover,the anti?proliferative effects against three human lung cancer cell lines of A549,HCC827,H1975 were assessed via MTT assay and the inhibitory activities against EGFR double mutant kinase(L858R/T790M)were tested by ADP?Glo assay.The results in vitro indicated that compounds TM1,TM2,TM4 displayed potent anti?proliferative activities against H1975 and HCC827 cell lines.The inhibitory activities of all the target compounds against EGFR mutant cells(HCC827 and H1975)were more potent than against wild?type EGFR cells(A549).Additionally,the IC50 values of TM1 and TM2 inhibited EGFRL858R/T790M reached 2.5 nmol·L^-1 and 2.0 nmol·L^-1,respectively,which were close to AZD9291(3.5 nmol·L^-1).The experimental results demonstrated that the designed and synthesized target compounds with purine skeleton displayed potent inhibitory activities against EGFR double?mutated cells and EGFR kinases.█.
作者
席肖肖
刘艳洁
黑媛媛
辛敏行
王璐
张三奇
XI Xiao?xiao;LIU Yan?jie;HEI Yuan?yuan;XIN Min?hang;WANG Lu;ZHANG San?qi(School of Pharmacy,Xi′an Jiaotong University,Xi′an 710061,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2020年第1期10-17,共8页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金项目(81803490).
