By modification of key carboxylate, hydrophobic, and zinc-binding groups projected from a sterically restricted terphenyl scaffold, a series of simple and nonpeptide mimetics of the Cys-Val-Ile-Met tetrapeptide substrate of protein farnesyltransferase (FTase) have been designed and synthesized. A crystal structure of 4-nitro-2-phenyl-3'-methoxycarbonylbiphenyl shows that the triphenyl fragment provides a large hydrophobic surface that potentially mimics the hydrophobic side chains of the three terminal residues in the tetrapeptide. 2-Phenyl-3-(N-(1-(4-eyanobenzyl)-1H-imidazol-5-yl)methyl)amino-3'carboxylbiphenyl, in which the free thiol group was replaced with a 1-(4-cyanobenzyl)imidazole group, shows submicromolar inhibition activity against FTase in vitro and inhibits H-Ras processing in whole cells.
机构:Univ Calif Berkeley, Dept Chem, Ctr New Direct Organ Synth, Berkeley, CA 94720 USA
Salisbury, Cleo M.
Ellman, Jonathan A.
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Univ Calif Berkeley, Dept Chem, Ctr New Direct Organ Synth, Berkeley, CA 94720 USAUniv Calif Berkeley, Dept Chem, Ctr New Direct Organ Synth, Berkeley, CA 94720 USA