title: Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation.
abstract: Nitrogenous bisphosphonate inhibitors of farnesyl disphosphate synthase have been used clinically for treatment of bone disease. Because many of their effects may be mediated by depletion of geranylgeranyl diphosphate, our group has sought compounds that do this more directly through inhibition of geranylgeranyl diphosphate synthase and we have discovered a number of isoprenoid-containing bisphosphonates that selectively inhibit this enzyme. These compounds have a high negative charge at physiological pH which is necessary for inhibition of the enzyme but may limit their ability to enter cells. Therefore, chemical modifications that mask this charge may enhance their cellular potency. We now have synthesized novel pivaloyloxymethyl-modified isoprenoid bisphosphonates and investigated their ability to inhibit protein geranylgeranylation within cells. We have found that addition of pivaloyloxymethyl moieties to isoprenoid bisphosphonates increases their potency towards cellular geranylgeranylation even though this modification decreases their in vitro inhibition of geranylgeranyl diphosphate synthase. Pivaloyloxymethyl modifications more effectively increase the cellular activity of the more polar isoprenoid bisphosphonates. These results reveal structural relationships between in vitro and cellular activity which may serve as the basis for future development of more potent and/or drug-like inhibitors of geranylgeranyl diphosphate synthase.
authors.affiliation: Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wiemer
authors.forename: Jose S
authors.initials: JS
authors.lastname: Yu
authors.forename: Larry W
authors.initials: LW
authors.lastname: Shull
authors.forename: Rocky J
authors.initials: RJ
authors.lastname: Barney
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wasko
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lamb
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Hohl
authors.forename: David F
authors.initials: DF
authors.lastname: Wiemer
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020014:K562 Cells; D008745:Methylation; D015394:Molecular Structure; D017368:Protein Prenylation / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry*
chemical_list: D004164:Diphosphonates; D013729:Terpenes