4-苯基-2-氨基嘧啶类化合物的设计合成及其抗肿瘤活性  

Design,synthesis and evaluation of novel 4-phenyl-2-aminopyrimidine derivatives as AKT inhibitors

作　　者：尹燕振 毛梽璎 黄碧涌 王璐颖[2] 王绍坤[2] 赵桂森[1] 

机构地区：[1]山东大学药学院药物化学研究所,山东济南250012 [2]山东大学药学院

出　　处：《中国药物化学杂志》2015年第3期168-174,共7页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21072115);山东大学大学生科技创新基金项目(2014354)

摘　　要：目的设计合成一系列4-苯基-2-氨基嘧啶类新型化合物,并测定其对前列腺癌细胞(PC-3)的生长抑制活性。方法以硝基苯乙酮为起始原料,通过嘧啶环合、酰胺缩合、硝基还原、氨基保护及脱保护反应合成目标化合物。采用MTT法测试化合物对前列腺癌PC-3细胞的生长抑制活性;采用均相时间分辨荧光法测定化合物对激酶AKT1的抑制活性。结果与结论合成了9个未见文献报道的4-苯基-2-氨基嘧啶类化合物,其结构经1H-NMR、MS谱确证。化合物9a-1、9a-3、9b-1(5μmol·L-1)对激酶AKT1的抑制率大于60%。Serine/threonine protein kinase B （AKT） plays an important role in the promotion of malignant tumor cell development, survival and metastasis. AKT has been suggested as one of the most attractive tar- gets for new anticancer drug development. Based on the analyses of the interaction between the ATP-compe- titive inhibitors and the binding sites of AKT, a series of 2-amino-4-phenylpyrimidine derivatives were de- signed and synthesized. The target compounds were obtained from nitrophenyl ethanone via 2-aminopyrimi- dine ring preparation, amidation reaction, reduction reaction, amino protection and deprotection reaction. The structures of the target compounds were identified by MS and 1H-NMR spectra. The results of biological evaluation indicated that compounds 9a-1,9a-3 and 9b-1 showed moderate antiproliferative activity against PC-3 cell lines and potent inhibitory activities against AKT1 with inhibition rates of 66. 60% ,66.57% and 61.35% at 5 μmol·L^-1 ,respectively.

关 键 词：4-苯基-2-氨基嘧啶衍生物 AKT抑制剂 合成 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]