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

摘要: Abstract The synthesis and evaluation of analogues key derivatives 10-CF 3 CO-DDACTHF as inhibitors glycinamide ribonucleotide transformylase (GAR Tfase) aminoimidazole carboxamide (AICAR are reported. Polyglutamate 1 were evaluated Escherichia coli recombinant human (rh) GAR Tfase, AICAR Tfase. Although the pentaglutamate 6 was found to be most active inhibitor series tested against rhGAR Tfase ( K i =0.004 μM), little distinction between mono–pentaglutamate observed =0.02–0.004 suggesting that principal role required polyglutamation is intracellular retention. In contrast, its defined polyglutamates – much less inactive when rhAICAR =65–0.120 μM) very selective (≥100-fold) for rh versus E. Additional examined 7 8 ) (1000-fold) highlighting exceptional characteristics .