Stereospecific synthesis and biological evaluation of farnesyl diphosphate isomers.
[formula: see text] A unified, stereospecific synthetic route to the three geometric isomers of (E,E)-farnesyl diphosphate (E,E-FPP) (1, 2, and 3) has been developed. The key feature of this synthesis is the ability to control the stereochemistry of triflation of the beta-ketoester 10 to give either 11 or 14. Preliminary evaluation of these compounds with protein-farnesyl transferase indicates that 1 and 2 are surprisingly effective substrates; however, Z,Z-FPP (3) is a poor substrate and a sub-micromolar inhibitor.
Shao
Y
Y
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan 48202, USA. rag@wizard.pharm.wayne.edu
Eummer
J T
JT
Gibbs
R A
RA
D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011106:Polyisoprenyl Phosphates / Q000138:chemical synthesis*; D012717:Sesquiterpenes; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D010088:Oxidoreductases; D013186:Farnesyl-Diphosphate Farnesyltransferase