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

8 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 - Apr 15 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, 15.04.2017, 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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