Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

Andrew J. Wiemer, Jose S. Yu, Larry W. Shull, Rocky J. Barney, Brian M. Wasko, Kimberly M. Lamb, Raymond J. Hohl, David F. Wiemer

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3652-3660
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number7
DOIs
StatePublished - Apr 1 2008

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Prenylation
Terpenes
Diphosphonates
Farnesyltranstransferase
Display devices
Protein Prenylation
Bone Diseases
Chemical modification
Enzymes
Masks
Bone
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Wiemer, A. J., Yu, J. S., Shull, L. W., Barney, R. J., Wasko, B. M., Lamb, K. M., ... Wiemer, D. F. (2008). Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. Bioorganic and Medicinal Chemistry, 16(7), 3652-3660. https://doi.org/10.1016/j.bmc.2008.02.016
Wiemer, Andrew J. ; Yu, Jose S. ; Shull, Larry W. ; Barney, Rocky J. ; Wasko, Brian M. ; Lamb, Kimberly M. ; Hohl, Raymond J. ; Wiemer, David F. / Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. In: Bioorganic and Medicinal Chemistry. 2008 ; Vol. 16, No. 7. pp. 3652-3660.
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Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation. / Wiemer, Andrew J.; Yu, Jose S.; Shull, Larry W.; Barney, Rocky J.; Wasko, Brian M.; Lamb, Kimberly M.; Hohl, Raymond J.; Wiemer, David F.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 7, 01.04.2008, p. 3652-3660.

Research output: Contribution to journalArticle

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T1 - Pivaloyloxymethyl-modified isoprenoid bisphosphonates display enhanced inhibition of cellular geranylgeranylation

AU - Wiemer, Andrew J.

AU - Yu, Jose S.

AU - Shull, Larry W.

AU - Barney, Rocky J.

AU - Wasko, Brian M.

AU - Lamb, Kimberly M.

AU - Hohl, Raymond J.

AU - Wiemer, David F.

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