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

doi:10.1016/j.bmc.2017.02.066

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Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

Journal article

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Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

Veronica S Wills, Joseph I Metzger, Cheryl Allen, Michelle L Varney, David F Wiemer and Sarah A Holstein

Bioorganic & medicinal chemistry, Vol.25(8), pp.2437-2444

04/15/2017

DOI: 10.1016/j.bmc.2017.02.066

PMCID: PMC5450914

PMID: 28302510

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https://www.ncbi.nlm.nih.gov/pmc/articles/5450914View

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Abstract

[Display omitted] 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.

Triazole

Bisphosphonate

Inhibition

GGDP synthase

Isoprenoid biosynthesis

Bishomoisoprenoids

Details

Title: Subtitle: Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase
Creators: Veronica S Wills - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Joseph I Metzger - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Cheryl Allen - Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
Michelle L Varney - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
David F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Sarah A Holstein - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry, Vol.25(8), pp.2437-2444
DOI: 10.1016/j.bmc.2017.02.066
PMID: 28302510
PMCID: PMC5450914
NLM abbreviation: Bioorg Med Chem
ISSN: 0968-0896
eISSN: 1464-3391
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: 01-224; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01CA-172070
Language: English
Date published: 04/15/2017
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9983985805702771

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