title: Divergent synthesis and identification of the cellular targets of deoxyelephantopins.
abstract: 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.
authors.affiliation: Department of Organic Chemistry, School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva 1211, Switzerland.
authors.forename: Roman
authors.initials: R
authors.lastname: Lagoutte
authors.affiliation: Department of Organic Chemistry, School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva 1211, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Serba
authors.affiliation: Department of Organic Chemistry, School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva 1211, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abegg
authors.affiliation: Department of Organic Chemistry, School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva 1211, Switzerland.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Hoch
authors.affiliation: Department of Organic Chemistry, School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva 1211, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Adibekian
authors.affiliation: Department of Organic Chemistry, School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva 1211, Switzerland.
authors.forename: Nicolas
authors.identifier: 0000-0003-1636-7766
authors.initials: N
authors.lastname: Winssinger
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003545:Cysteine / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000032:analysis / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D011994:Recombinant Proteins / Q000378:metabolism; D012717:Sesquiterpenes / Q000032:analysis / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D016335:Zinc Fingers / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D047495:PPAR gamma; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C528427:deoxyelephantopin; D003545:Cysteine