Several strategies for synthesis of nonracemic dimethyl α-(hydroxyfarnesyl)phosphonate and the
parent phosphonic acid have been explored. Separation of diastereomeric derivatives prepared by
esterification of racemic α-hydroxy phosphonate with (S)-(+)-O-methylmandelic acid was possible,
and these diastereomers could be assigned absolute stereochemistry on the basis of literature
precedent. However, hydrolysis to the α-hydroxy phosphonic acid was accompanied by extensive
isomerization. Addition of a nonracemic phosphonamidite to farnesal also gave nonracemic material,
but again hydrolysis was problematic. Oxidation of dimethyl farnesylphosphonate anion with
nonracemic (camphorsulfonyl)oxaziridines was shown to be regio- and stereoselective for formation
of the α-hydroxy phosphonate. Enantiomeric excess of ∼70% ee was established by conversion of
the oxidation products to their (S)-(+)-O-methylmandelate derivatives. Although hydrolysis of these
methyl esters was accompanied by extensive racemization, both enantiomers of α-(hydroxyfarnesyl)phosphonic acid were obtained in low ee by this strategy.
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.
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