ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors

Nazmul H. Bhuiyan, Michelle L. Varney, Deep S. Bhattacharya, William M. Payne, Aaron M. Mohs, Sarah A. Holstein, David F. Wiemer

Research output: Contribution to journalArticle

Abstract

The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the in vivo biodistribution of HA-conjugated GGDPS inhibitors.

Original languageEnglish (US)
Article number126633
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number19
DOIs
StatePublished - Oct 1 2019

Fingerprint

Farnesyltranstransferase
Terpenes
Diphosphonates
Plasma Cells
Protein Prenylation
Plasmas
Proteins
Triazoles
Protein Transport
Hyaluronic Acid
Multiple Myeloma
Enzymes

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

ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors. / Bhuiyan, Nazmul H.; Varney, Michelle L.; Bhattacharya, Deep S.; Payne, William M.; Mohs, Aaron M.; Holstein, Sarah A.; Wiemer, David F.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 19, 126633, 01.10.2019.

Research output: Contribution to journalArticle

Bhuiyan, Nazmul H. ; Varney, Michelle L. ; Bhattacharya, Deep S. ; Payne, William M. ; Mohs, Aaron M. ; Holstein, Sarah A. ; Wiemer, David F. / ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2019 ; Vol. 29, No. 19.
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