Synthesis and biological evaluation of a series of aromatic bisphosphonates

Rocky J Barney; Brian M Wasko; Amel Dudakovic; Raymond J Hohl; David F Wiemer

doi:10.1016/j.bmc.2010.08.036

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Synthesis and biological evaluation of a series of aromatic bisphosphonates

Journal article

Peer reviewed

Synthesis and biological evaluation of a series of aromatic bisphosphonates

Rocky J Barney, Brian M Wasko, Amel Dudakovic, Raymond J Hohl and David F Wiemer

Bioorganic & medicinal chemistry, Vol.18(20), pp.7212-7220

2010

DOI: 10.1016/j.bmc.2010.08.036

PMID: 20832326

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https://doi.org/10.7270/q2s46s55View

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Abstract

A series of isoprenoid bisphosphonates has been prepared where an aromatic ring has been used to replace one of the isoprenoid olefins. These compounds have been investigated for their ability to inhibit protein geranylgeranylation in enzyme assays and within cells. Geminal bisphosphonates display varied biological activity depending on the nature of the substituents on the central carbon atom. For example, the nitrogenous bisphosphonates zoledronate and risedronate inhibit the enzyme farnesyl diphosphate synthase while digeranyl bisphosphonate has been shown to inhibit the enzyme geranylgeranyl diphosphate synthase. We now have synthesized isoprenoid bisphosphonates where an aromatic ring has been used to replace one of the isoprenoid olefins in an isoprenoid bisphosphonate and investigated the ability of these new compounds to impair protein geranylgeranylation within cells. Several of these new compounds are potent inhibitors of the enzyme geranylgeranyl diphosphate synthase.

Enzyme inhibitor

Bisphosphonate

Geranylgeranyl diphosphate

Isoprenoid biosynthesis

GGDPS

Protein prenylation

Details

Title: Subtitle: Synthesis and biological evaluation of a series of aromatic bisphosphonates
Creators: Rocky J Barney - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Brian M Wasko - Program in Molecular and Cell Biology, University of Iowa, Iowa City, IA 52242-1294, USA
Amel Dudakovic - Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1294, USA
Raymond J Hohl - Program in Molecular and Cell Biology, University of Iowa, Iowa City, IA 52242-1294, 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.18(20), pp.7212-7220
DOI: 10.1016/j.bmc.2010.08.036
PMID: 20832326
NLM abbreviation: Bioorg Med Chem
ISSN: 0968-0896
eISSN: 1464-3391
Publisher: Elsevier Ltd
Language: English
Date published: 2010
Academic Unit: Neuroscience and Pharmacology; Chemistry; Internal Medicine
Record Identifier: 9983985870002771

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