Design, Synthesis, and Evaluation of Su- gar Amino Acid Based Inhibitors of Pro- tein Prenyl Transferases PFT and PGGT-1

Eleven analogues of the C-terminal Ca1a2X motif found in natural substrates of the prenyl transferases PFT and PGGT-1 were synthesized and evaluated for their inhibition potency and selectivity against PFT and PGGT-1. Replacement of the central dipeptide part a1a2 by a benzylated sugar amino acid resulted in a good and highly selective PFT inhibitor (8, IC50 = 250 ± 20 nM). The methyl ester of 8 (13) selectively inhibited protein farnesylation in cultured cells.