Design and synthesis of a transferable farnesyl pyrophosphate analogue to Ras by protein farnesyltransferase

Kareem A.H. Chehade, Douglas A. Andres, Hiromi Morimoto, H. Peter Spielmann

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55 Scopus citations


The posttranslational addition of a farnesyl moiety to the Ras oncoprotein is essential for its membrane localization and is required for both its biological activity and ability to induce malignant transformation. We describe the design and synthesis of a farnesyl pyrophosphate (FPP) analogue, 8-anilinogeranyl pyrophosphate 3 (AGPP), in which the ω-terminal isoprene unit of the farnesyl group has been replaced with an aniline functionality. The key steps in the synthesis are the reductive amination of the α,β-unsaturated aldehyde 5 to form the lipid analogue 6, and the subsequent conversion of the allylic alcohol 7 to the chloride 8 via Ph3PCl2 followed by displacement with [(n-Bu)4N]3-HP2O7 to give AGPP (3). AGPP is a substrate for protein farnesyltransferase (FTase) and is transferred to Ras by FTase with the same kinetics as the natural substrate, FPP. AGPP is highly selective, showing little inhibitory activity against either geranylgeranyl-protein transferase type I (GGTase I) (K(i) = 0.06 μM, IC50 = 20 μM) or squalene synthase (IC50 = 1000 μM). AGPP is the first efficiently transferable analogue of FPP to be modified at the ω-terminus that provides a platform from which additional analogues can be made to probe the biological function of protein farnesylation. AGPP is the first example of a class of compounds that are alternate substrates for protein isoprenylation that are not inhibitors of squalene synthase.

Original languageEnglish
Pages (from-to)3027-3033
Number of pages7
JournalJournal of Organic Chemistry
Issue number10
StatePublished - May 19 2000

ASJC Scopus subject areas

  • Organic Chemistry


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