Cheng Heng, Chong Youhoon, Hwang Inkyu, Tavassoli Ali, Zhang Yan, Wilson Ian A, Benkovic Stephen J, Boger Dale L
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bioorg Med Chem. 2005 May 16;13(10):3577-85. doi: 10.1016/j.bmc.2004.12.004.
The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, K(i) = 0.23 microM), 10-methanesulfonyl-5-DACTHF (2, K(i) = 0.58 microM), and 10-methylthio-DDACTHF (3, K(i) = 0.25 microM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC50 = 1.0 microM and 2, IC50 = 2.0 microM).
报道了10-甲磺酰基-DDACTHF（1）、10-甲磺酰基-5-DACTHF（2）和10-甲硫基-DDACTHF（3）作为甘氨酰胺核糖核苷酸转甲酰基酶（GAR Tfase）和氨基咪唑甲酰胺核糖核苷酸转甲酰基酶（AICAR Tfase）潜在抑制剂的合成及评估。发现化合物10-甲磺酰基-DDACTHF（1，K(i)=0.23微摩尔）、10-甲磺酰基-5-DACTHF（2，K(i)=0.58微摩尔）和10-甲硫基-DDACTHF（3，K(i)=0.25微摩尔）是重组人GAR Tfase的选择性强效抑制剂。其中，3对CCRF-CEM细胞系表现出异常强效的、嘌呤敏感的生长抑制活性（3，IC50 = 100纳摩尔），其效力比洛美曲唑高3倍，比母体未取代的DDACTHF高30倍，而1和2表现出更适度的生长抑制活性（1，IC50 = 1.0微摩尔；2，IC50 = 2.0微摩尔）。
