Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase

Sarah A Holstein, Diana M. Cermak, David F. Wiemer, Kriste Lewis, Raymond J. Hohl

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Several phosphonate and bisphosphonate analogues of farnesyl pyrophosphate have been prepared for an examination of their ability to inhibit farnesyl protein transferase (FPTase). A Horner-Wadsworth-Emmons condensation of farnesal or geranial with tetraethyl methylenediphosphonate gave the desired vinyl phosphonates, while alkylation of the dimethyl methylphosphonate anion with a terpenoid bromide gave the corresponding saturated phosphonates. Alkylation of tetraethyl methylenediphosphonate with farnesyl bromide gave the expected alkyl bisphosphonate, which was converted to its α,β-unsaturated derivative by preparation of the phenyl selenide, oxidation to the selenoxide, and elimination. In a similar fashion, triethyl phosphonoacetate was converted to a farnesyl pyrophosphate analogue by reaction with farnesyl bromide. After preparation of the respective acids, each compound was tested for inhibition of FPTase at concentrations ranging up to 10μM. The effect of these compounds on FPTase activity varied substantially, ranging from depressed to surprisingly enhanced enzymatic activity. Copyright (C) 1998 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)687-694
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume6
Issue number6
DOIs
StatePublished - Jan 1 1998

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Organophosphonates
Diphosphonates
Transferases
Bromides
citral
Alkylation
Proteins
Terpenes
Anions
Condensation
Derivatives
Oxidation
Acids
farnesyl pyrophosphate

Keywords

  • FPTase
  • Farnesyl pyrophosphate
  • Inhibitor
  • Ras

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase. / Holstein, Sarah A; Cermak, Diana M.; Wiemer, David F.; Lewis, Kriste; Hohl, Raymond J.

In: Bioorganic and Medicinal Chemistry, Vol. 6, No. 6, 01.01.1998, p. 687-694.

Research output: Contribution to journalArticle

Holstein, Sarah A ; Cermak, Diana M. ; Wiemer, David F. ; Lewis, Kriste ; Hohl, Raymond J. / Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase. In: Bioorganic and Medicinal Chemistry. 1998 ; Vol. 6, No. 6. pp. 687-694.
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