α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Robert A. Matthiesen, Michelle L. Varney, Pauline C. Xu, Alex S. Rier, David F. Wiemer, Sarah A Holstein

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates.

Original languageEnglish (US)
Pages (from-to)376-385
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number2
DOIs
StatePublished - Jan 15 2018

Fingerprint

Farnesyltranstransferase
Triazoles
Methylation
Terpenes
Diphosphonates
Protein Prenylation
Stereochemistry
Prodrugs
Alkenes
Multiple Myeloma
Proteins
Carbon
Salts
Neoplasms
Therapeutics

Keywords

  • 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

α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. / Matthiesen, Robert A.; Varney, Michelle L.; Xu, Pauline C.; Rier, Alex S.; Wiemer, David F.; Holstein, Sarah A.

In: Bioorganic and Medicinal Chemistry, Vol. 26, No. 2, 15.01.2018, p. 376-385.

Research output: Contribution to journalArticle

Matthiesen, Robert A. ; Varney, Michelle L. ; Xu, Pauline C. ; Rier, Alex S. ; Wiemer, David F. ; Holstein, Sarah A. / α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. In: Bioorganic and Medicinal Chemistry. 2018 ; Vol. 26, No. 2. pp. 376-385.
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