A new motif for inhibitors of geranylgeranyl diphosphate synthase

Benjamin J Foust; Cheryl Allen; Sarah A Holstein; David F Wiemer

doi:10.1016/j.bmc.2016.06.019

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A new motif for inhibitors of geranylgeranyl diphosphate synthase

Journal article

Open access

Peer reviewed

A new motif for inhibitors of geranylgeranyl diphosphate synthase

Benjamin J Foust, Cheryl Allen, Sarah A Holstein and David F Wiemer

Bioorganic & medicinal chemistry, Vol.24(16), pp.3734-3741

08/15/2016

DOI: 10.1016/j.bmc.2016.06.019

PMCID: PMC4955788

PMID: 27338660

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http://doi.org/10.1016/j.bmc.2016.06.019View

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Abstract

[Display omitted] The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure–function relationship which is dependent on the nature of the alkyl group at the α-carbon.

Inhibition

Prodrug

Bisphosphonate monoester

GGDP synthase

Isoprenoid biosynthesis

Details

Title: Subtitle: A new motif for inhibitors of geranylgeranyl diphosphate synthase
Creators: Benjamin J Foust - 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
Sarah A Holstein - Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
David F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry, Vol.24(16), pp.3734-3741
DOI: 10.1016/j.bmc.2016.06.019
PMID: 27338660
PMCID: PMC4955788
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: 08/15/2016
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9983985827802771

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