Farnesyl diphosphate (FPP) is a 15 carbon molecule that serves key roles in biology. It provides the carbon skeletons for sesquiterpene natural products and the sidechains for various cofactors. Dimerization of FPP leads to the production of cholesterol while linkage to protein-derived cysteine residues yields prenylated proteins. Photoactive analogues of FPP have been useful to identify proteins that interact with FPP and to map their binding sites. A variety of photoactive groups have been appended to various isoprenoid scaffolds to create such compounds including aryl azides, diazotrifluropropionates and benzophenones. Recently, we reported on diazirine-based analogues to probe the enzymes involved in the processing of prenylated proteins. Here we describe the synthesis and application of related probes that mimic isoprenoid diphosphates. FPP and related geranylgeranyl diphosphate (GGPP) probes (<b>1</b> and <b>2</b>, respectively) were prepared in 7 steps from farnesol and geranylgeraniol. Both analogues were inhibitors of protein farnesyltransferase and labeled the enzyme upon photolysis. They also labeled the protein SmgGDS, a modulator of protein prenylation. We are currently extending these studies to probe other proteins that interact with FPP.

Synthesis and applications of photoactive analogues of isoprenoid diphosphates incorporating diazirines

253rd National Meeting (2017)

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