Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Alisa E.R. Fairweather, Daniel B. Goetz, Chloe M. Schroeder, Nazmul H. Bhuiyan, Michelle L. Varney, David F. Wiemer, Sarah A. Holstein

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Agents that inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS) have anti-cancer activity and our prior studies have investigated the structure-function relationship for a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors. To further explore this structure-function relationship, a series of novel α-modified triazole phosphonates was prepared and evaluated for activity as GGDPS inhibitors in enzyme and cell-based assays. These studies revealed flexibility at the α position of the bisphosphonate derivatives with respect to being able to accommodate a variety of substituents without significantly affecting potency compared to the parent unsubstituted inhibitor. However, the monophosphonate derivatives lacked activity. These studies further our understanding of the structure-function relationship of the triazole-based GGDPS inhibitors and lay the foundation for future studies evaluating the impact of α-modifications on in vivo activity.

Original languageEnglish (US)
Article number116307
JournalBioorganic and Medicinal Chemistry
Volume44
DOIs
StatePublished - Aug 15 2021

Keywords

  • Bisphosphonate
  • Geranylgeranyl diphosphate synthase
  • Inhibition
  • Isoprenoid biosynthesis
  • Myeloma
  • Triazole

ASJC Scopus subject areas

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

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