Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids

R J Hohl; K A Lewis; D M Cermak; D F Wiemer

doi:10.1007/s11745-998-0178-x

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Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids

Journal article

Peer reviewed

Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids

R J Hohl, K A Lewis, D M Cermak and D F Wiemer

Lipids, Vol.33(1), pp.39-46

01/1998

DOI: 10.1007/s11745-998-0178-x

PMID: 9470172

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Abstract

This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-alpha-Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-alpha-hydroxyfarnesyl- and alpha-hydroxygeranylphosphonates. A striking find is that only E,E-alpha-hydroxyfarnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-alpha-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-alpha-hydroxyfarnesylphosphonate is greater in enzyme than intact cell assays. This active compound does not significantly inhibit geranylgeranyl protein transferase I or squalene synthase, nor does it diminish cholesterol synthesis. These results indicate that the length of the terpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synthase by E,E-alpha-hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.

Protein Prenylation - drug effects

Farnesol - metabolism

Farnesol - pharmacology

Humans

Leukemia

Molecular Conformation

Alkyl and Aryl Transferases - metabolism

Enzyme Inhibitors - pharmacology

Alkyl and Aryl Transferases - antagonists & inhibitors

Organophosphonates - metabolism

Substrate Specificity

ras Proteins - metabolism

Structure-Activity Relationship

Farnesyl-Diphosphate Farnesyltransferase - metabolism

Organophosphonates - pharmacology

Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors

Organophosphonates - chemistry

Farnesol - analogs & derivatives

Tumor Cells, Cultured

Cholesterol - biosynthesis

Farnesol - chemistry

Details

Title: Subtitle: Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids
Creators: R J Hohl - Department of Internal Medicine, University of Iowa, Iowa City 52242, USA. raymond-hohl@uiowa.edu
K A Lewis
D M Cermak
D F Wiemer
Resource Type: Journal article
Publication Details: Lipids, Vol.33(1), pp.39-46
Publisher: United States
DOI: 10.1007/s11745-998-0178-x
PMID: 9470172
ISSN: 0024-4201
eISSN: 1558-9307
Language: English
Date published: 01/1998
Academic Unit: Neuroscience and Pharmacology; Chemistry; Internal Medicine
Record Identifier: 9983985702502771

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