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Bioorg Med Chem. 2014 May 1;22(9):2791-8. doi: 10.1016/j.bmc.2014.03.014. Epub 2014 Mar 24.

Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase.

Author information

1
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA.
2
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
3
Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: david-wiemer@uiowa.edu.
4
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.

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.

KEYWORDS:

GGDP synthase; Inhibition; Isoprenoid biosynthesis; Olefin stereochemistry

PMID:
24726306
PMCID:
PMC4067939
DOI:
10.1016/j.bmc.2014.03.014
[Indexed for MEDLINE]
Free PMC Article

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