Synthesis and biochemical evaluation of 3,7-disubstituted farnesyl diphosphate analogues.
Farnesyl diphosphate (FPP) analogues have proven to be both potent inhibitors of protein-farnesyltransferase (FTase) and valuable probes for the investigation of the function of prenylated proteins. Previously, we have demonstrated that certain 3-substituted and 7-substituted FPP analogues can act as inhibitors of FTase, while others are effective alternative substrates. We have now utilized our vinyl triflate-mediated route to synthesize the first seven FPP variants bearing substituents in both the 3- and 7-positions of the isoprene unit. Despite their exceptional steric bulk with respect to FPP itself, six of the seven analogues bind to FTase. Two of the analogues are potent inhibitors of the enzyme, but a more striking finding is that three FPP variants (4a, 4b, and 4f) are efficient alternative substrates for FTase.
Rawat
Diwan S
DS
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Krzysiak
Amanda J
AJ
Gibbs
Richard A
RA
D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011106:Polyisoprenyl Phosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate