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

12 Citations (Scopus)

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

Fingerprint

Farnesyltranstransferase
Triazoles
Diphosphonates
Protein Prenylation
Terpenes
Stereochemistry
Proteins
Alkenes
Protein Transport
Multiple Myeloma
Chain length
Isomers
Availability
Apoptosis
Pharmaceutical Preparations

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

Cite this

Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase. / Wills, Veronica S.; Metzger, Joseph I.; Allen, Cheryl; Varney, Michelle L.; Wiemer, David F.; Holstein, Sarah A.

In: Bioorganic and Medicinal Chemistry, Vol. 25, No. 8, 01.01.2017, p. 2437-2444.

Research output: Contribution to journalArticle

Wills, Veronica S. ; Metzger, Joseph I. ; Allen, Cheryl ; Varney, Michelle L. ; Wiemer, David F. ; Holstein, Sarah A. / Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase. In: Bioorganic and Medicinal Chemistry. 2017 ; Vol. 25, No. 8. pp. 2437-2444.
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