Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate.
Three isoprenoid diphosphate analogues of farnesyl diphosphate (FPP) where the diphosphate has been replaced by methylene diphosphonate and the negative charges masked by frangible pivaloyloxymethyl (POM) esters were prepared. Farnesyl methylenediphosphonate is a sub-micromolar substrate for protein farnesyl transferase. The tripivaloyloxymethyl esters of isoprenoid methylenediphosphonate have significantly increased lipophilicity and may act as important farnesyl diphosphate prodrugs.
Troutman
Jerry M
JM
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536-0084, USA.
Chehade
Kareem A H
KA
Kiegiel
Katarzyna
K
Andres
Douglas A
DA
Spielmann
H Peter
HP
D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D051231:Farnesyltranstransferase; D011106:Polyisoprenyl Phosphates / Q000138:chemical synthesis* / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D012717:Sesquiterpenes; D012995:Solubility; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000138:chemical synthesis
D011106:Polyisoprenyl Phosphates; D011355:Prodrugs; D012717:Sesquiterpenes; D013729:Terpenes; C004808:farnesyl pyrophosphate; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase