647833-58-7Relevant academic research and scientific papers
Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
Desharnais, Joel,Hwang, Inkyu,Zhang, Yan,Tavassoli, Ali,Baboval, Justin,Benkovic, Stephen J.,Wilson, Ian A.,Boger, Dale L.
, p. 4511 - 4521 (2007/10/03)
The synthesis and evaluation of analogues and key derivatives of 10-CF 3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 was found to be the most active inhibitor of the series tested against rhGAR Tfase (Ki=0.004 μM), little distinction between the mono-pentaglutamate derivatives was observed (K i=0.02-0.004 μM), suggesting that the principal role of the required polyglutamation of 1 is intracellular retention. In contrast, 1 and its defined polyglutamates 3-6 were much less inactive when tested against rhAICAR Tfase (Ki=65-0.120 μM) and very selective (≥100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1.
