Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

The synthesis and evaluation of analogues and key derivatives of 10-CF3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Polyglutamate analogues of I 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 (K-i = 0.004 muM), little distinction between the mono-pentaglutamate derivatives was observed (K-i = 0.02-0.004 muM), 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 (K-i = 65-0.120 muM) and very selective (greater than or equal to 100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of I were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1. (C) 2003 Elsevier Ltd. All rights reserved.