Journal article
Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase
Bioorganic & medicinal chemistry, Vol.6(6), pp.687-694
1998
DOI: 10.1016/S0968-0896(98)00034-0
PMID: 9681134
Abstract
Several phosphonate and bisphosphonate analogues of farnesyl pyrophosphate have been prepared for an examination of their ability to inhibit farnesyl protein transferase (FPTase). A Horner–Wadsworth–Emmons condensation of farnesal or geranial with tetraethyl methylenediphosphonate gave the desired vinyl phosphonates, while alkylation of the dimethyl methylphosphonate anion with a terpenoid bromide gave the corresponding saturated phosphonates. Alkylation of tetraethyl methylenediphosphonate with farnesyl bromide gave the expected alkyl bisphosphonate, which was converted to its α,β-unsaturated derivative by preparation of the phenyl selenide, oxidation to the selenoxide, and elimination. In a similar fashion, triethyl phosphonoacetate was converted to a farnesyl pyrophosphate analogue by reaction with farnesyl bromide. After preparation of the respective acids, each compound was tested for inhibition of FPTase at concentrations ranging up to 10 μM. The effect of these compounds on FPTase activity varied substantially, ranging from depressed to surprisingly enhanced enzymatic activity.
Details
- Title: Subtitle
- Phosphonate and bisphosphonate analogues of farnesyl pyrophosphate as potential inhibitors of farnesyl protein transferase
- Creators
- Sarah A Holstein - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, USADiana M Cermak - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, USADavid F Wiemer - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, USAKriste Lewis - Departments of Internal Medicine and Pharmacology, University of Iowa, Iowa City, Iowa 52242-1294, USARaymond J Hohl - Departments of Internal Medicine and Pharmacology, University of Iowa, Iowa City, Iowa 52242-1294, USA
- Resource Type
- Journal article
- Publication Details
- Bioorganic & medicinal chemistry, Vol.6(6), pp.687-694
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/S0968-0896(98)00034-0
- PMID
- 9681134
- ISSN
- 0968-0896
- eISSN
- 1464-3391
- Language
- English
- Date published
- 1998
- Academic Unit
- Neuroscience and Pharmacology; Chemistry; Internal Medicine
- Record Identifier
- 9983985866502771
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