title: A new motif for inhibitors of geranylgeranyl diphosphate synthase.
abstract: The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure-function relationship which is dependent on the nature of the alkyl group at the α-carbon.
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Foust
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Allen
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Holstein
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA; Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA. Electronic address: david-wiemer@uiowa.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: Wiemer
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase
keywords: Bisphosphonate monoester; GGDP synthase; Inhibition; Isoprenoid biosynthesis; Prodrug