Synthesis, Biochemical, and Cellular Evaluation of Farnesyl Monophosphate Prodrugs as Farnesyltransferase Inhibitors

Certain farnesyl diphosphate (FPP) analogs are potent inhibitors of the potential anticancer drug target protein farnesyltransferase (FTase), but these compounds are not suitable as drug candidates. Thus, phosphoramidate prodrug derivatives of the monophosphate precursors of FPP-based FTase inhibito...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-07, Vol.50 (14), p.3274-3282
Main Authors: Clark, Michelle K, Scott, Sarah A, Wojtkowiak, Jonathan, Chirco, Rosemarie, Mathieu, Patricia, Reiners, John J, Mattingly, Raymond R, Borch, Richard F, Gibbs, Richard A
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Cell Line
Cell Proliferation - drug effects
Chromatography, High Pressure Liquid
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Farnesyltranstransferase - antagonists & inhibitors
General aspects
Magnetic Resonance Spectroscopy
Medical sciences
Pharmacology. Drug treatments
Polyisoprenyl Phosphates - chemical synthesis
Polyisoprenyl Phosphates - pharmacology
Prodrugs - chemical synthesis
Prodrugs - pharmacology
Spectrometry, Mass, Electrospray Ionization
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Summary:Certain farnesyl diphosphate (FPP) analogs are potent inhibitors of the potential anticancer drug target protein farnesyltransferase (FTase), but these compounds are not suitable as drug candidates. Thus, phosphoramidate prodrug derivatives of the monophosphate precursors of FPP-based FTase inhibitors have been synthesized. The monophosphates themselves were significantly more potent inhibitors of FTase than the corresponding FPP analogs. The effects of the prodrug 5b (a derivative of 3-allylfarnesyl monophosphate) have been evaluated on prenylation of RhoB and on the cell cycle in a human malignant schwannoma cell line (STS-26T). In combination treatments, 1−3 μM 5b plus 1 μM lovastatin induced a significant inhibition of RhoB prenylation, and a combination of these drugs at 1 μM each also resulted in significant cell cycle arrest in G1. Indeed, combinations as low as 50 nM lovastatin + 1 μM 5c or 250 nM lovastatin + 50 nM 5c were highly cytostatic in STS-26T cell culture.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0701829