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Natural product–inspired cascade synthesis yields modulators of centrosome integrity

Nature Chemical Biology volume 8, pages 179–184 (2012)Cite this article

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Abstract

In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product–inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10–30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.

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Figure 1: Inspiration and synthesis design for indoloquinolizine compound collections.
Figure 2: Influence of (R)-16a on chromosome congression, spindle pole formation and progression of mitosis in HeLa cells.
Figure 3: Identification and validation of NPM and Crm1 as target proteins of 17.

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Acknowledgements

We would like to thank T.U. Mayer (Universität Konstanz) for helpful discussions, S. Müller and T. Klüßendorf (Max-Planck-Institut Dortmund) for assistance with the fluorescence lifetime imaging microscopy measurements, C. Nowak for technical assistance, S.J. Martin (Smurfit Institute of Genetics, Trinity College Dublin) for the pET19b-NPM plasmid, A. Wittinghofer (Max-Planck-Institut Dortmund) for the pET3a–Crm1 vector and the Dortmund Protein Facility for cloning NPM-citrine. This work was supported by the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 268309 to H.W.) and by the Max Planck Gesellschaft.

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Author notes

  1. Sascha Menninger

    Present address: Present address: Lead Discovery Center GmbH, Dortmund, Germany.,

  2. Heiko Dückert and Verena Pries: These authors contributed equally to this work.

Authors and Affiliations

  1. Abteilung Chemische Biologie, Max-Planck-Institut für Molekulare Physiologie, Dortmund, Germany

    Heiko Dückert, Verena Pries, Vivek Khedkar, Sascha Menninger, Hanna Bruss, Andreas Brockmeyer, Petra Janning, Katja Hübel, Slava Ziegler, Kamal Kumar & Herbert Waldmann

  2. Technische Universität Dortmund, Fakultät Chemie, Chemische Biologie, Dortmund, Germany

    Heiko Dückert, Verena Pries, Sascha Menninger, Hanna Bruss, Kamal Kumar & Herbert Waldmann

  3. Max-Planck-Institut für Molekulare Zellbiologie und Genetik, Dresden, Germany

    Alexander W Bird, Zoltan Maliga & Anthony Hyman

  4. Chemisches Institut, Westfälische Wilhelms-Universität, Münster, Germany

    Stefan Grimme

  5. Technische Universität Dortmund, Fakultät Chemie, Anorganische Chemie, Dortmund, Germany

    Markus Schürmann & Hans Preut

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Contributions

H.D., V.K. and H.B. designed and performed the synthesis experiments. V.P., S.M., A.W.B., Z.M. and S.Z. carried out the biological studies. P.J. and A.B. performed MS analysis. H.W., K.K., K.H., S.Z. and A.H. designed experiments. M.S. and H.P. carried out the X-ray crystallographic analysis. S.G. determined the absolute configuration of 16a. H.W., K.K. and S.Z. supervised the project and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Kamal Kumar or Herbert Waldmann.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 4086 kb)

Supplementary Movie 1

The movie file shows division of U20S expressing mCherry-α-tubulin (MPG 2388 kb)

Supplementary Movie 2

The movie file shows multipolar division in U20S expressing mCherry-α-tubulin treated with 30 μM 16a (MPG 7408 kb)

Supplementary Movie 3

The movie file shows mitosis in HeLa cells expressing GFP-histone 2B. (MPG 1654 kb)

Supplementary Movie 4

The movie file shows prolonged mitosis in HeLa cells expressing GFP-histone 2B treated with 30 μM 16a (MPG 2806 kb)

Crystal Structure Data 1—Indoloquinolizine 16a

Waldmann_SI_Indoloquinolizine 16a.CIF (CIF 18 kb)

Crystal Structure Data 1—Intermediate 12b

Waldmann_SI_Intermediate 12b.CIF (CIF 18 kb)

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Dückert, H., Pries, V., Khedkar, V. et al. Natural product–inspired cascade synthesis yields modulators of centrosome integrity. Nat Chem Biol 8, 179–184 (2012). https://doi.org/10.1038/nchembio.758

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