Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold.
J Med Chem, 2002/1/03;45(1):177-88.
Ohkanda J[1], Lockman JW, Kothare MA, Qian Y, Blaskovich MA, Sebti SM, Hamilton AD
Affiliations
PMID: 11754590
Impact factor: 8.039
Abstract
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-cyanobenzyl)-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.
MeSH terms
3T3 Cells; Alkyl and Aryl Transferases; Animals; Blotting, Western; Crystallography, X-Ray; Enzyme Inhibitors; Genes, ras; Hydrophobic and Hydrophilic Interactions; Mice; Molecular Mimicry; Oligopeptides; Protein Prenylation; Stereoisomerism; Structure-Activity Relationship; Zinc; rap1 GTP-Binding Proteins
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