STEREOCHEMISTRY-DEPENDENT INHIBITION OF RAS FARNESYLATION BY FARNESYLPHOSPHONIC-ACIDS

This investigation compares the effects of three farnesyl pyrophosphat e analogs on selected aspects of isoprenoid metabolism. E,E-alpha-Hydr oxyfarnesylphosphonate was prepared by an improved variation on a lite rature synthesis, which also gave access to the new Z,E-alpha-hydroxyf arnesyl- and alpha-hydroxygeranylphosphonates. A striking find is that only E,E-alpha-hydroxyfarnesylphosphonate induces alteration of RAS p rocessing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-alpha-farnesyl- a nd geranylphosphonates are inactive. The inhibitory activity of E,E-al pha-hydroxyfarnesylphosphonate is greater in enzyme than intact cell a ssays. This active compound does not significantly inhibit geranylgera nyl protein transferase I or squalene synthase, nor does it diminish c holesterol synthesis. These results indicate that the length of the te rpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synth ase by E,E-alpha-hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.