Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

Veronica S. Wills, Joseph I. Metzger, Cheryl Allen, Michelle L. Varney, David F. Wiemer, Sarah A. Holstein

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Protein geranylgeranylation reactions are dependent on the availability of geranylgeranyl diphosphate (GGDP), which serves as the isoprenoid donor. Inhibition of GGDP synthase (GGDPS) is of interest from a drug development perspective as GGDPS inhibition results in impaired protein geranylgeranylation, which in multiple myeloma, disrupts monoclonal protein trafficking and induces apoptosis. We have recently reported a series of isoprenoid triazole bisphosphonates and have demonstrated that a 3:1 mixture of homogeranyl and homoneryl isomers potently, and in a synergistic manner, inhibits GGDPS. We now present the synthesis and biological evaluation of a novel series of bishomoisoprenoid triazoles which furthers our understanding of the structure-function relationship of this class. These studies demonstrate the importance of chain length and olefin stereochemistry on inhibitory activity.

Original languageEnglish (US)
Pages (from-to)2437-2444
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume25
Issue number8
DOIs
StatePublished - Jan 1 2017

Keywords

  • Bishomoisoprenoids
  • Bisphosphonate
  • GGDP synthase
  • Inhibition
  • Isoprenoid biosynthesis
  • Triazole

ASJC Scopus subject areas

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

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