Divergent synthesis and identification of the cellular targets of deoxyelephantopins

Herbal extracts containing sesquiterpene lactones have been extensively used in traditional medicine and are known to be rich in α,β-unsaturated functionalities that can covalently engage target proteins. Here we report synthetic methodologies to access analogues of deoxyelephantopin, a sesquiterpen...

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Bibliographic Details
Published in:Nature communications 2016-08, Vol.7 (1), p.12470-12470, Article 12470
Main Authors: Lagoutte, Roman, Serba, Christelle, Abegg, Daniel, Hoch, Dominic G., Adibekian, Alexander, Winssinger, Nicolas
Format: Article
Language:English
Subjects:
639/638/309
639/638/403/977
639/638/92
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Cysteine - metabolism
Humanities and Social Sciences
Humans
Kinases
Lactones - analysis
Lactones - chemical synthesis
Lactones - pharmacology
Lactones - therapeutic use
Molecular Targeted Therapy - methods
multidisciplinary
Natural products
Neoplasms - drug therapy
PPAR gamma - antagonists & inhibitors
PPAR gamma - metabolism
Proteins
Proteomics
Proteomics - methods
Recombinant Proteins - metabolism
Science
Science (multidisciplinary)
Sesquiterpenes - analysis
Sesquiterpenes - chemical synthesis
Sesquiterpenes - pharmacology
Sesquiterpenes - therapeutic use
Zinc Fingers - drug effects
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Summary:Herbal extracts containing sesquiterpene lactones have been extensively used in traditional medicine and are known to be rich in α,β-unsaturated functionalities that can covalently engage target proteins. Here we report synthetic methodologies to access analogues of deoxyelephantopin, a sesquiterpene lactone with anticancer properties. Using alkyne-tagged cellular probes and quantitative proteomics analysis, we identified several cellular targets of deoxyelephantopin. We further demonstrate that deoxyelephantopin antagonizes PPARγ activity in situ via covalent engagement of a cysteine residue in the zinc-finger motif of this nuclear receptor. Deoxyelephantopin is a naturally occurring sesquiterpene lactone with known anticancer properties. Here, the authors synthesize deoxyelephantopins and a range of analogues including alkyne-tagged probes, using them to identify its cellular targets.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms12470