Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold

J. Ohkanda, J. W. Lockman, M. A. Kothare, Y. Qian, M. A. Blaskovich, S. M. Sebti, Andrew Hamilton

Research output: Contribution to journalArticle

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 CysVal-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.

Original languageEnglish (US)
Pages (from-to)177-188
Number of pages12
JournalJournal of Medicinal Chemistry
Volume45
Issue number1
DOIs
StatePublished - Jan 3 2002

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Farnesyltranstransferase
Sulfhydryl Compounds
Scaffolds
Zinc
Crystal structure
Substrates
Processing
imidazole
p21(ras) farnesyl-protein transferase
In Vitro Techniques

ASJC Scopus subject areas

  • Organic Chemistry

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Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold. / Ohkanda, J.; Lockman, J. W.; Kothare, M. A.; Qian, Y.; Blaskovich, M. A.; Sebti, S. M.; Hamilton, Andrew.

In: Journal of Medicinal Chemistry, Vol. 45, No. 1, 03.01.2002, p. 177-188.

Research output: Contribution to journalArticle

Ohkanda, J. ; Lockman, J. W. ; Kothare, M. A. ; Qian, Y. ; Blaskovich, M. A. ; Sebti, S. M. ; Hamilton, Andrew. / Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 1. pp. 177-188.
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