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Divergent Synthesis and Identification of the Cellular Targets Of ARTICLE Received 11 Jan 2016 | Accepted 23 Jun 2016 | Published 19 Aug 2016 DOI: 10.1038/ncomms12470 OPEN Divergent synthesis and identification of the cellular targets of deoxyelephantopins Roman Lagoutte1,*, Christelle Serba1,*, Daniel Abegg1,*, Dominic G. Hoch1, Alexander Adibekian1 & Nicolas Winssinger1 Herbal extracts containing sesquiterpene lactones have been extensively used in traditional medicine and are known to be rich in a,b-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 PPARg activity in situ via covalent engagement of a cysteine residue in the zinc-finger motif of this nuclear receptor. 1 Department of Organic Chemistry, School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest-Ansermet, Geneva 1211, Switzerland. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to A.A. (email: [email protected]) or to N.W. (email: [email protected]). NATURE COMMUNICATIONS | 7:12470 | DOI: 10.1038/ncomms12470 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms12470 he contribution of natural products to our current issues in kinase inhibition, or efficacy in protease inhibition, have pharmacopeia and to the identification of important led to a recent reconsideration of covalent inhibitors6–8. Natural Ttherapeutic targets is well recognized1,2. While natural products have played a key role in the drug-discovery process products are the result of a long evolutionary optimization, a and as probes in chemical biology9. This privileged role has number of examples have demonstrated that synthetic inspired many efforts to access natural-product-like libraries by modifications beyond the biosynthetically accessible analogues conventional or diversity-oriented synthesis10–13. Terpenoids and can bring about important pharmacological improvements. sesquiterpene lactones certainly stand out for their historical use Success stories starting with the semisynthetic derivatization in medicine and are rich in mildly reactive functionalities that can of 6-aminopenicillanic acid to enhance b-lactam activity, to engage in a covalent interactions14,15. Indeed, functional groups the conversion of erythromycin into azithromycin or baccatin such as a-methylene-g-butyrolactone, a,b-unsaturated reactive III into taxotere have inspired tremendous efforts in natural ester chain and epoxides are preponderant in this natural product product synthesis. While a significant portion of bioactive family and are at the source of its rich biological activity16–18. natural products are endowed with reactive functionalities that For example, both helenalin (Fig. 1) and parthenolide inhibit the can engage in covalent interactions with their target, the NF-kB pathway by covalently inactivating their target19.In historic reluctance to develop covalent inhibitor has curtailed the case of helenalin, this inhibition has been proposed to result interest in this subset of natural products. In a number of from a covalent crosslinking of two cysteines in p65. Helenalin cases, these mildly reactive groups are pivotal to the compound’s is broadly used as an anti-inflammatory drug in the form bioactivity. Despite the potential for promiscuous covalent of its natural extract from Arnica. Thapsigargin is widely engagement through unspecific reactions, a number of covalent used in cellular biology and covalently inhibits SERCA inhibitors display useful selectivity with regards to their targeted (Sarco/endoplasmic reticulum Ca2 þ ATPase)20. Arglabin protein3,4 by virtue of the fact that at low inhibitor concentration inhibits protein farnesylation without affecting protein gerany- (mM), the kinetics of unspecific reaction are slow compared lation. On the basis of the critical role of farnesylation for H-Ras with the reaction resulting from a specific inhibitor–target function (an important oncogenic driver), this compound has interaction (that is, high effective concentration of reagents). been shown to be an effective antitumour agent21 and a dimethyl The preponderance of such reactive groups amongst secondary amine prodrug of this natural compound is currently used metabolites would suggest that there is an evolutionary advantage therapeutically. Most recently, a-methylene-g-butyrolactones to covalent inhibition. For instance, a covalent inhibitor may also showed promising antibacterial activity by covalently also be important in displacing an otherwise unfavourable binding to critical transcriptional regulators and inhibiting the equilibrium with an endogenous ligand5. The declining virulence of Staphylococcus aureus22. pipeline of traditional small-molecule drugs coupled to the Extracts of the plant Elephantopus scaber have long been used benefit of covalent binding to overcome resistance/selectivity in traditional medicine with deoxyelephantopin being the most Selected bioactive sesquiterpene lactones OAc H O O O 6 H O O O O 2 O O OH OH H O OH O O Helenalin Thapsigargin NF-κB inhibitor SERCA inhibitor O Arglabin O O O O O O O O O O 10 2 8 O O O 4 6 O O O O O O O Deoxyelephantopin Isodeoxyelephantopin Elephantopin Carbonylation OH I 1 O Barbier reaction Br RCM O 2 O Figure 1 | Bioactive covalent sesquiterpenes and retrosynthetic analysis of deoxyelephantopins. Selected examples of bioactive sesquiterpene interacting covalently with their target; structure and retrosynthetic analysis of deoxyelephantopins. 2 NATURE COMMUNICATIONS | 7:12470 | DOI: 10.1038/ncomms12470 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/ncomms12470 ARTICLE active component23. Recently, deoxyelephantopin has been of the methacrylate side chain (10) provided an intermediate that shown to be more effective than paclitaxel in suppressing did afford nordeoxyelephantopin in the RCM with the desired tumour growth and metastasis in a murine orthotopic breast E-alkene geometry. Interestingly, the RCM proceeded only under cancer model24. At the cellular level, deoxyelephantopin has the action of first generation catalyst (Grubbs I). Furthermore, been shown to be cytotoxic at doses of 0.5–2 mgmlÀ 1 in several only the diastereomer corresponding to deoxyelephantopin human cancer cell lines. While there is evidence that relative stereochemistry afforded the cyclization product, the deoxyelephantopin inhibits the NF-kB pathway24,25, proteomics C-2 epimer failed to give cyclization. A high correlation analysis of up- and downregulated proteome in treated cells between nordeoxyelephantopin and deoxyelephantopin NMR suggested it also suppressed proteasome activity26. Moreover, coupling constants suggests that the two products have very SPR experiments suggest that deoxyelephantopin can act as a similar dihedral angles along the 10-membered ring and partial agonist of PPARg27, a nuclear receptor that is well hence, a comparable conformation. Furthermore, comparison of known to be involved in pathologies of obesity, diabetes and NOESY spectra showed similar interactions between the protons atherosclerosis and thus represents a major pharmacological on either face of the 10-membered ring for both compounds target. However, it is not clear whether this natural product (Supplementary Figs 1 and 2). With these ring-closing conditions can also engage PPARg directly in cells. While these in hand, the same strategy was pursued to access analogues activities could be rationalized by diverse covalent target wherein one of the exocyclic conjugate acceptors was reduced engagement, a proteome-wide identification of direct cellular (11 and 12 respectively). While the same reaction starting with 3b targets of deoxyelephantopin has not been performed to date. afforded the cyclization precursor (not shown), no cyclization The impressive in vitro and in vivo activities reported for product was observed under a variety of metathesis conditions. deoxyelephantopin coupled to its historical use as a traditional To control the stereochemistry at C-2, we first explored remedy demands a better understanding of its reactivity recent chemistry for enantioselective alkyne addition35, however, profile in a cellular setting and covalent protein target(s). substrate 3a proved problematic based on its propensity to Perhaps, due to its abundance from natural extracts, there isomerize under Lewis acidic conditions. As an alternative, is no total synthesis of deoxyelephantopin reported to date nor substrate 13 was converted to the furan 14, which underwent a structure-activity relationship for this promising therapeutic. palladium-catalysed decarboxylative asymmetric allylic Here we report synthetic methodologies to access analogues alkylation (DAAA)36,37 using Trost’s ligand to afford 6 in of deoxyelephantopins, including alkyne-tagged cellular either stereochemistry with 92:8 er.38 Enantiomerically enriched probes for quantitative proteomics analysis. We identified (R)-6 was used to obtain nordeoxyelephantopin in four steps several cellular targets of deoxyelephantopin and demonstrated while (S)-6 (obtained with the (R,R)-DACH-phenyl catalyst—not that deoxyelephantopin antagonizes PPARg activity through shown) afforded the ent-nordeoxyelephantopin.
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