Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Andrew J Wiemer; Jose S Yu; Kimberly M Lamb; Raymond J Hohl; David F Wiemer

doi:10.1016/j.bmc.2007.09.029

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Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Journal article

Peer reviewed

Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Andrew J Wiemer, Jose S Yu, Kimberly M Lamb, Raymond J Hohl and David F Wiemer

Bioorganic & medicinal chemistry, Vol.16(1), pp.390-399

2008

DOI: 10.1016/j.bmc.2007.09.029

PMID: 17905588

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https://doi.org/10.7270/q26m37ppView

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Abstract

Nitrogenous bisphosphonates are used clinically to reduce bone resorption associated with osteoporosis or metastatic bone disease, and are recognized as inhibitors of farnesyl diphosphate synthase. Inhibition of this enzyme decreases cellular levels of both farnesyl diphosphate and geranylgeranyl diphosphate which results in a variety of downstream biological effects including inhibition of protein geranylgeranylation. Our lab recently has prepared several isoprenoid bisphosphonates that inhibit protein geranylgeranylation and showed that one selectively inhibits geranylgeranyl diphosphate synthase. This results in depletion of intracellular geranylgeranyl diphosphate and impacts protein geranylgeranylation but does not affect protein farnesylation. To clarify the structural features of isoprenoid bisphosphonates that account for their geranylgeranyl diphosphate synthase inhibition, we have prepared a new group of isoprenoid bisphosphonates. The complete set of compounds has been tested for in vitro inhibition of human recombinant geranylgeranyl diphosphate synthase and cellular inhibition of protein geranylgeranylation. These results show some surprising relationships between in vitro and cellular activity, and will guide development of clinical agents directed at geranylgeranyl diphosphate synthase.

Rap1a

Prenylation

Bisphosphonate

Ras

Farnesylation

Geranylgeranyl diphosphate

Geranylgeranylation

Geranylgeranyl diphosphate synthase

Farnesyl diphosphate

Details

Title: Subtitle: Mono- and dialkyl isoprenoid bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
Creators: Andrew J Wiemer - Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA 52242-1294, USA
Jose S Yu - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Kimberly M Lamb - Department of Internal Medicine, University of Iowa, Iowa City, IA 52242-1294, USA
Raymond J Hohl - Interdisciplinary Program in Molecular and Cellular 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.16(1), pp.390-399
DOI: 10.1016/j.bmc.2007.09.029
PMID: 17905588
NLM abbreviation: Bioorg Med Chem
ISSN: 0968-0896
eISSN: 1464-3391
Publisher: Elsevier Ltd
Language: English
Date published: 2008
Academic Unit: Neuroscience and Pharmacology; Chemistry; Internal Medicine
Record Identifier: 9983985954302771

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