Pivaloyloxtmethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

Date

2008

Authors

Wasko, Brian

Journal Title

Journal ISSN

Volume Title

Publisher

Biorg Med Chem

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 and cellular activity which may serve as the basis for future development of more potent and/or drug-like inhibitors of geranylgeranyl diphosphate synthase

Description

Keywords

Bisphosphonate, Geranylgeranyl diphosphate, Geranylgeranyl pyrophosphate, Geranylgeranyl diphosphate synthase, Farnesyl diphosphate, Ras Rap1a, Prenylation, Geranylgeranylation, Prodrug, Pivaloyloxymethyl, POM

Citation

Wiemer AJ, Yu JS, Shull LW, Barney RJ, Wasko BM, Lamb KM, Hohl RJ, and Wiemer DF. Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. Bioorg Med Chem. 2008 Apr 1;16(7):3652-60