Journal article
Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase
Bioorganic & medicinal chemistry, Vol.25(8), pp.2437-2444
04/15/2017
DOI: 10.1016/j.bmc.2017.02.066
PMCID: PMC5450914
PMID: 28302510
Abstract
[Display omitted] Protein geranylgeranylation reactions are dependent on the availability of geranylgeranyl diphosphate (GGDP), which serves as the isoprenoid donor. Inhibition of GGDP synthase (GGDPS) is of interest from a drug development perspective as GGDPS inhibition results in impaired protein geranylgeranylation, which in multiple myeloma, disrupts monoclonal protein trafficking and induces apoptosis. We have recently reported a series of isoprenoid triazole bisphosphonates and have demonstrated that a 3:1 mixture of homogeranyl and homoneryl isomers potently, and in a synergistic manner, inhibits GGDPS. We now present the synthesis and biological evaluation of a novel series of bishomoisoprenoid triazoles which furthers our understanding of the structure-function relationship of this class. These studies demonstrate the importance of chain length and olefin stereochemistry on inhibitory activity.
Details
- Title: Subtitle
- Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase
- Creators
- Veronica S Wills - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USAJoseph I Metzger - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USACheryl Allen - Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USAMichelle L Varney - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USADavid F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USASarah A Holstein - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Resource Type
- Journal article
- Publication Details
- Bioorganic & medicinal chemistry, Vol.25(8), pp.2437-2444
- DOI
- 10.1016/j.bmc.2017.02.066
- PMID
- 28302510
- PMCID
- PMC5450914
- NLM abbreviation
- Bioorg Med Chem
- ISSN
- 0968-0896
- eISSN
- 1464-3391
- Publisher
- Elsevier Ltd
- Grant note
- DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: 01-224; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01CA-172070
- Language
- English
- Date published
- 04/15/2017
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9983985805702771
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