Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl)benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway
Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl)benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway
复制标题
DOI：
10.1016/j.bmc.2004.11.049
复制
发表时间：
2005-05-16
影响因子：
3.5
通讯作者：
Boger, DL
中科院分区：
文献类型：
--
作者：
Cheng, H;Hwang, I;Boger, DL
报道了甘氨酰胺核糖肽转换酶(GAR Tfase)和氨基咪唑甲酰胺核糖核苷酸转换酶(AICAR Tfase)的抑制剂N-{4-[5-(2，4-diamino-6-oxo-1，6-dihydropyrimidin-5-yl)-2-(2，2，2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic酸(2)的合成和评价。缓蚀剂2是由甲基4-(4，4，4-trifluoro-3-dimethylhydrazonobutyl)benzoate与1-氯-3-碘丙烷C-烷基化，然后构筑嘧啶酮环聚合而成的。化合物2对重组人GAR Tfase有较强的抑制作用(K-I=0.50µM)，而对大肠杆菌GAR Tfase和重组人AICAR Tfase均无抑制作用(K-I>；100 mU M)。化合物2对CCRF-CEM细胞具有中等的嘌呤敏感生长抑制活性(IC50=6.0mM)。(C)2005爱思唯尔有限公司。保留所有权利。
The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid (2) as an inhibitor of glycinamide ribonuelcotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (K-i = 0.50 mu M), whereas it was inactive (K-i > 100 mu M) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 mu M). (c) 2005 Elsevier Ltd. All rights reserved.