TY - JOUR
T1 - Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids
AU - Hohl, Raymond J.
AU - Lewis, Kriste A.
AU - Cermak, Diana M.
AU - Wiemer, David F.
N1 - Funding Information:
This work was supported by grants from the Roy J. Carver Charitable Trust, Leukemia Society of America, and University of Iowa Cancer Center. R. Hohl is a recipient of an American Society of Clinical Oncology Young Investigator Award and a Pharmaceutical Research and Manufacturers of America Foundation Faculty Development Award in Clinical Pharmacology. We thank Sarah Holstein, Department of Chemistry at the University of Iowa, for preparation of (E,E)-(4,8,12-trimethyl-3,7,11-tridecatrienylidene)bisphosphonic acid. The RPMI-8402 cells were provided by M. Diaz, Loyola University.
PY - 1998
Y1 - 1998
N2 - This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-α- Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-α- hydroxyfarnesyl- and α-hydroxy-geranylphosphonates. A striking find is that only E,E-α-hydroxy-farnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-α-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-α- 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-α- hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.
AB - This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-α- Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-α- hydroxyfarnesyl- and α-hydroxy-geranylphosphonates. A striking find is that only E,E-α-hydroxy-farnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-α-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-α- 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-α- hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.
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U2 - 10.1007/s11745-998-0178-x
DO - 10.1007/s11745-998-0178-x
M3 - Article
C2 - 9470172
AN - SCOPUS:0031933368
SN - 0024-4201
VL - 33
SP - 39
EP - 46
JO - Lipids
JF - Lipids
IS - 1
ER -