2-(Acyloxy)ethylphosphonate analogues of prenyl pyrophosphates: synthesis and biological characterization

Diana M. Cermak, David F. Wiemer, Kriste Lewis, Raymond Hohl

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

2-(Acyloxy)ethylphosphonate analogues of geranyl, farnesyl, and geranylgeranyl pyrophosphate have been prepared. Horner-Wadsworth-Emmons condensation of different terpene aldehydes with an unsymmetrical bisphosphonate was the key step in syntheses of the phosphonates bearing α,β-unsaturated acyloxy groups. After preparation of the respective phosphonic acids through reaction with TMSBr, both acids and esters were tested for their effects on DNA synthesis in human-derived myeloid and lymphoid leukemia cell lines. The phosphonate esters varied substantially in their ability to impair proliferation of the different cell lines, but testing against one possible target, farnesyl protein transferase (FPTase), revealed little impact at concentrations ranging up to 10μM. Because the corresponding 2,3-dihydro compounds showed similar biological activity, conjugate addition would not appear to be involved in the toxicity. Copyright (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)2729-2737
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume8
Issue number12
DOIs
StatePublished - Nov 27 2000

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Organophosphonates
Diphosphates
Phosphorous Acids
Esters
Bearings (structural)
Cells
Lymphoid Leukemia
Cell Line
Myeloid Leukemia
Terpenes
Diphosphonates
Transferases
Bioactivity
Aldehydes
Toxicity
Condensation
Lymphocytes
Acids
DNA
Testing

All Science Journal Classification (ASJC) codes

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

Cite this

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abstract = "2-(Acyloxy)ethylphosphonate analogues of geranyl, farnesyl, and geranylgeranyl pyrophosphate have been prepared. Horner-Wadsworth-Emmons condensation of different terpene aldehydes with an unsymmetrical bisphosphonate was the key step in syntheses of the phosphonates bearing α,β-unsaturated acyloxy groups. After preparation of the respective phosphonic acids through reaction with TMSBr, both acids and esters were tested for their effects on DNA synthesis in human-derived myeloid and lymphoid leukemia cell lines. The phosphonate esters varied substantially in their ability to impair proliferation of the different cell lines, but testing against one possible target, farnesyl protein transferase (FPTase), revealed little impact at concentrations ranging up to 10μM. Because the corresponding 2,3-dihydro compounds showed similar biological activity, conjugate addition would not appear to be involved in the toxicity. Copyright (C) 2000 Elsevier Science Ltd.",
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2-(Acyloxy)ethylphosphonate analogues of prenyl pyrophosphates : synthesis and biological characterization. / Cermak, Diana M.; Wiemer, David F.; Lewis, Kriste; Hohl, Raymond.

In: Bioorganic and Medicinal Chemistry, Vol. 8, No. 12, 27.11.2000, p. 2729-2737.

Research output: Contribution to journalArticle

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T1 - 2-(Acyloxy)ethylphosphonate analogues of prenyl pyrophosphates

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AU - Wiemer, David F.

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AU - Hohl, Raymond

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N2 - 2-(Acyloxy)ethylphosphonate analogues of geranyl, farnesyl, and geranylgeranyl pyrophosphate have been prepared. Horner-Wadsworth-Emmons condensation of different terpene aldehydes with an unsymmetrical bisphosphonate was the key step in syntheses of the phosphonates bearing α,β-unsaturated acyloxy groups. After preparation of the respective phosphonic acids through reaction with TMSBr, both acids and esters were tested for their effects on DNA synthesis in human-derived myeloid and lymphoid leukemia cell lines. The phosphonate esters varied substantially in their ability to impair proliferation of the different cell lines, but testing against one possible target, farnesyl protein transferase (FPTase), revealed little impact at concentrations ranging up to 10μM. Because the corresponding 2,3-dihydro compounds showed similar biological activity, conjugate addition would not appear to be involved in the toxicity. Copyright (C) 2000 Elsevier Science Ltd.

AB - 2-(Acyloxy)ethylphosphonate analogues of geranyl, farnesyl, and geranylgeranyl pyrophosphate have been prepared. Horner-Wadsworth-Emmons condensation of different terpene aldehydes with an unsymmetrical bisphosphonate was the key step in syntheses of the phosphonates bearing α,β-unsaturated acyloxy groups. After preparation of the respective phosphonic acids through reaction with TMSBr, both acids and esters were tested for their effects on DNA synthesis in human-derived myeloid and lymphoid leukemia cell lines. The phosphonate esters varied substantially in their ability to impair proliferation of the different cell lines, but testing against one possible target, farnesyl protein transferase (FPTase), revealed little impact at concentrations ranging up to 10μM. Because the corresponding 2,3-dihydro compounds showed similar biological activity, conjugate addition would not appear to be involved in the toxicity. Copyright (C) 2000 Elsevier Science Ltd.

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