Synthesis, biochemical, and cellular evaluation of farnesyl monophosphate prodrugs as farnesyltransferase inhibitors.
Certain farnesyl diphosphate (FPP) analogs are potent inhibitors of the potential anticancer drug target protein farnesyltransferase (FTase), but these compounds are not suitable as drug candidates. Thus, phosphoramidate prodrug derivatives of the monophosphate precursors of FPP-based FTase inhibitors have been synthesized. The monophosphates themselves were significantly more potent inhibitors of FTase than the corresponding FPP analogs. The effects of the prodrug 5b (a derivative of 3-allylfarnesyl monophosphate) have been evaluated on prenylation of RhoB and on the cell cycle in a human malignant schwannoma cell line (STS-26T). In combination treatments, 1-3 microM 5b plus 1 microM lovastatin induced a significant inhibition of RhoB prenylation, and a combination of these drugs at 1 microM each also resulted in significant cell cycle arrest in G1. Indeed, combinations as low as 50 nM lovastatin + 1 microM 5c or 250 nM lovastatin + 50 nM 5c were highly cytostatic in STS-26T cell culture.
Clark
Michelle K
MK
Medicinal Chemistry and Molecular Pharmacology and Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Scott
Sarah A
SA
Wojtkowiak
Jonathan
J
Chirco
Rosemarie
R
Mathieu
Patricia
P
Reiners
John J
JJ
Mattingly
Raymond R
RR
Borch
Richard F
RF
Gibbs
Richard A
RA
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D011106:Polyisoprenyl Phosphates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
D004791:Enzyme Inhibitors; D011106:Polyisoprenyl Phosphates; D011355:Prodrugs; C059195:farnesyl monophosphate; D051231:Farnesyltranstransferase