Development of a tripeptide mimetic strategy for the inhibition of protein farnesyltransferase

Mohit A. Kotharé, Junko Ohkanda, Jeffrey W. Lockman, Yimin Qian, Michelle A. Blaskovich, Said M. Sebti, Andrew D. Hamilton

Research output: Contribution to journalArticlepeer-review

Abstract

This paper describes the development of a novel terphenyl-based tripeptide mimetic of the CAAX carboxy terminal sequence of Ras. We employ a concise synthesis to form a series of differently functionalized terphenyl inhibitors of protein farnesyltransferase (PFTase), exemplified by 5, 6 and 7. The key reaction in the synthesis of the terphenyl methyl ester 13, and therefore 6 and 7, was the Pd-catalyzed chemoselective Suzuki cross-coupling of 3-bromo-4-chloronitrobenzene 16 with an appropriate boronic acid derivative utilizing a commercially available, electron rich phosphine ligand. We further show that one member of this series is a potent inhibitor of PFTase. (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)9833-9841
Number of pages9
JournalTetrahedron
Volume56
Issue number50
DOIs
StatePublished - Dec 8 2000

Keywords

  • Aryl chloride
  • Boronic acid
  • Chemoselective Suzuki cross-coupling
  • Inhibitor
  • Phosphine ligand
  • Protein farnesyltransferase (PFTase)
  • Terphenyl scaffold

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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