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 Hamilton

Research output: Contribution to journalArticle

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
StatePublished - Dec 8 2000

Fingerprint

phosphine
Boronic Acids
Esters
Electrons
Ligands
Derivatives
p21(ras) farnesyl-protein transferase
4-chloronitrobenzene

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

Cite this

Kotharé, M. A., Ohkanda, J., Lockman, J. W., Qian, Y., Blaskovich, M. A., Sebti, S. M., & Hamilton, A. (2000). Development of a tripeptide mimetic strategy for the inhibition of protein farnesyltransferase. Tetrahedron, 56(50), 9833-9841.

Development of a tripeptide mimetic strategy for the inhibition of protein farnesyltransferase. / Kotharé, Mohit A.; Ohkanda, Junko; Lockman, Jeffrey W.; Qian, Yimin; Blaskovich, Michelle A.; Sebti, Said M.; Hamilton, Andrew.

In: Tetrahedron, Vol. 56, No. 50, 08.12.2000, p. 9833-9841.

Research output: Contribution to journalArticle

Kotharé, MA, Ohkanda, J, Lockman, JW, Qian, Y, Blaskovich, MA, Sebti, SM & Hamilton, A 2000, 'Development of a tripeptide mimetic strategy for the inhibition of protein farnesyltransferase', Tetrahedron, vol. 56, no. 50, pp. 9833-9841.
Kotharé MA, Ohkanda J, Lockman JW, Qian Y, Blaskovich MA, Sebti SM et al. Development of a tripeptide mimetic strategy for the inhibition of protein farnesyltransferase. Tetrahedron. 2000 Dec 8;56(50):9833-9841.
Kotharé, Mohit A. ; Ohkanda, Junko ; Lockman, Jeffrey W. ; Qian, Yimin ; Blaskovich, Michelle A. ; Sebti, Said M. ; Hamilton, Andrew. / Development of a tripeptide mimetic strategy for the inhibition of protein farnesyltransferase. In: Tetrahedron. 2000 ; Vol. 56, No. 50. pp. 9833-9841.
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