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Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellular targets of eupalmerin acetate

Nature Chemistry volume 5, pages 510–517 (2013)Cite this article

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A Corrigendum to this article was published on 20 June 2013

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Abstract

Natural products have a venerable history of, and enduring potential for the discovery of useful biological activity. To fully exploit this, the development of chemical methodology that can functionalize unique sites within these complex structures is highly desirable. Here, we describe the use of rhodium(II)-catalysed C–H amination reactions developed by Du Bois to carry out simultaneous structure–activity relationship studies and arming (alkynylation) of natural products at ‘unfunctionalized’ positions. Allylic and benzylic C–H bonds in the natural products undergo amination while olefins undergo aziridination, and tertiary amine-containing natural products are converted to amidines by a C–H amination–oxidation sequence or to hydrazine sulfamate zwitterions by an unusual N-amination. The alkynylated derivatives are ready for conversion into cellular probes that can be used for mechanism-of-action studies. Chemo- and site-selectivity was studied with a diverse library of natural products. For one of these—the marine-derived anticancer diterpene, eupalmerin acetate—quantitative proteome profiling led to the identification of several protein targets in HL-60 cells, suggesting a polypharmacological mode of action.

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Figure 1
Figure 2: Synthesis of alkynyl sulfamate 9.
Figure 3: Natural product remodelling.
Figure 4: Cytoxicity and proteomic profiling of EuPA and EuPAyne.

Change history

  • 22 May 2013

    In the print version of this paper, the stereochemical configuration of the β-lactone starting material 7 is drawn incorrectly ((R)-(–)-3-hydroxy-4,4,4-trichlorobutyric β-lactone purchased from Aldrich was used in this work). As a result, the stereochemical configurations of compounds 8 and 9 and the structure of the R group in Table 1 are also drawn incorrectly. These errors have now been corrected in HTML and PDF versions of this Article.

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Acknowledgements

The authors acknowledge support from the National Institutes of Health (NIH, GM806307, to D.R.; CA087660, to B.C.; GM086271, to A.D.R.), the Welch Foundation (A-1280, to D.R.), a Ray Kathren American Cancer Society fellowship (to J.S.C.) and a Ruth L. Kirschstein National Research Service Award (F32GM095245-01 to J.S.C.). The Office of the Vice President for Research, the College of Science and the Department of Chemistry at Texas A&M provided seed funding for the TAMU Natural Products LINCHPIN Laboratory. The authors thank S. Serna and J. Rodríguez (Monterrey Institute of Technology) for providing the parthenin used in these studies, and J. Reibenspies and W. Russell for X-ray crystallographic and mass data, respectively.

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Authors and Affiliations

  1. Department of Chemistry, Texas A&M University, PO Box 30012, College Station, 77842-3012, Texas, USA

    Jing Li, Cong-Ying Zhou, Howard Williams & Daniel Romo

  2. Natural Products LINCHPIN Laboratory, Texas A&M University, PO Box 30012, College Station, 77842-3012, Texas, USA

    Jing Li & Daniel Romo

  3. Scripps Research Institute, The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Justin S. Cisar & Benjamin F. Cravatt

  4. Department of Chemistry, University of Puerto Rico, Río Piedras Campus, PO Box 23346, San, PR 00931-3346, Juan, Puerto Rico

    Brunilda Vera & Abimael D. Rodríguez

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Contributions

D.R. and B.F.C. jointly conceived the study and supervised the work. D.R., B.F.C., J.L., J.S.C. and C.Z. were involved with the design of the studies, performance of the experiments, and analysis of the results. J.L., J.S.C. and D.R. wrote the manuscript. H.W. assisted with acquisition and analysis of 2D and cryoprobe NMR data. A.D.R. and B.V. isolated and purified samples of eupalmerolide and EuPA and assisted with the NMR analysis of the resultant alkynylated derivatives. All authors edited the manuscript.

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Correspondence to Daniel Romo.

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Crystallographic data for compound 23a (CIF 64 kb)

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Li, J., Cisar, J., Zhou, CY. et al. Simultaneous structure–activity studies and arming of natural products by C–H amination reveal cellular targets of eupalmerin acetate. Nature Chem 5, 510–517 (2013). https://doi.org/10.1038/nchem.1653

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