Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

Xiang Zhou, Sarah D. Ferree, Veronica S. Wills, Ella J. Born, Huaxiang Tong, David F. Wiemer, Sarah A. Holstein

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

When inhibitors of enzymes that utilize isoprenoid pyrophosphates are based on the natural substrates, a significant challenge can be to achieve selective inhibition of a specific enzyme. One element in the design process is the stereochemistry of the isoprenoid olefins. We recently reported preparation of a series of isoprenoid triazoles as potential inhibitors of geranylgeranyl transferase II but these compounds were obtained as a mixture of olefin isomers. We now have accomplished the stereoselective synthesis of these triazoles through the use of epoxy azides for the cycloaddition reaction followed by regeneration of the desired olefin. Both geranyl and neryl derivatives have been prepared as single olefin isomers through parallel reaction sequences. The products were assayed against multiple enzymes as well as in cell culture studies and surprisingly a Z-olefin isomer was found to be a potent and selective inhibitor of geranylgeranyl diphosphate synthase.

Original languageEnglish (US)
Pages (from-to)2791-2798
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number9
DOIs
StatePublished - May 1 2014

Fingerprint

Farnesyltranstransferase
Triazoles
Diphosphonates
Alkenes
Terpenes
Isomers
Stereochemistry
Azides
Cycloaddition
Diphosphates
Cycloaddition Reaction
Enzyme Inhibitors
Enzymes
Cell culture
Regeneration
Cell Culture Techniques
Derivatives
Substrates

Keywords

  • GGDP synthase
  • Inhibition
  • Isoprenoid biosynthesis
  • Olefin stereochemistry

ASJC Scopus subject areas

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

Cite this

Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase. / Zhou, Xiang; Ferree, Sarah D.; Wills, Veronica S.; Born, Ella J.; Tong, Huaxiang; Wiemer, David F.; Holstein, Sarah A.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 9, 01.05.2014, p. 2791-2798.

Research output: Contribution to journalArticle

Zhou, Xiang ; Ferree, Sarah D. ; Wills, Veronica S. ; Born, Ella J. ; Tong, Huaxiang ; Wiemer, David F. ; Holstein, Sarah A. / Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 9. pp. 2791-2798.
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AU - Ferree, Sarah D.

AU - Wills, Veronica S.

AU - Born, Ella J.

AU - Tong, Huaxiang

AU - Wiemer, David F.

AU - Holstein, Sarah A.

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