Journal article
Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase
Bioorganic & medicinal chemistry, Vol.22(9), pp.2791-2798
05/01/2014
DOI: 10.1016/j.bmc.2014.03.014
PMCID: PMC4067939
PMID: 24726306
Abstract
When inhibitors of enzymes that utilize isoprenoid pyrophosphates are based on the natural substrates, a significant challenge can be to achieve selective inhibition of a specific enzyme. One element in the design process is the stereochemistry of the isoprenoid olefins. We recently reported preparation of a series of isoprenoid triazoles as potential inhibitors of geranylgeranyl transferase II but these compounds were obtained as a mixture of olefin isomers. We now have accomplished the stereoselective synthesis of these triazoles through the use of epoxy azides for the cycloaddition reaction followed by regeneration of the desired olefin. Both geranyl and neryl derivatives have been prepared as single olefin isomers through parallel reaction sequences. The products were assayed against multiple enzymes as well as in cell culture studies and surprisingly a Z-olefin isomer was found to be a potent and selective inhibitor of geranylgeranyl diphosphate synthase.
Details
- Title: Subtitle
- Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase
- Creators
- Xiang Zhou - Department of Chemistry, University of Iowa, Iowa City, IA 52242, USASarah D Ferree - Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USAVeronica S Wills - Department of Chemistry, University of Iowa, Iowa City, IA 52242, USAElla J Born - Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USAHuaxiang Tong - Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USADavid F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242, USASarah A Holstein - Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Bioorganic & medicinal chemistry, Vol.22(9), pp.2791-2798
- DOI
- 10.1016/j.bmc.2014.03.014
- PMID
- 24726306
- PMCID
- PMC4067939
- NLM abbreviation
- Bioorg Med Chem
- ISSN
- 0968-0896
- eISSN
- 1464-3391
- Publisher
- Elsevier BV
- Grant note
- name: University of Iowa Graduate College; DOI: 10.13039/100012675, name: Center for Biocatalysis and Bioprocessing; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, and the NIH
- Language
- English
- Date published
- 05/01/2014
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9983985960902771
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