Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Natural product–inspired cascade synthesis yields modulators of centrosome integrity


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Kumar, K. & Waldmann, H. Synthesis of natural product inspired compound collections. Angew. Chem. Int. Ed. Engl. 48, 3224–3242 (2009).

    Article  CAS  Google Scholar 

  2. Nören-Muller, A. et al. Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. Proc. Natl. Acad. Sci. USA 103, 10606–10611 (2006).

    Article  Google Scholar 

  3. Antonchick, A.P. et al. Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products. Nat. Chem. 2, 735–740 (2010).

    Article  CAS  Google Scholar 

  4. Wetzel, S., Bon, R.S., Kumar, K. & Waldmann, H. Biology oriented synthesis. Angew. Chem. Int. Ed. Engl. 50, 10800–10826 (2011).

    Article  CAS  Google Scholar 

  5. Bon, R.S. & Waldmann, H. Bioactivity-guided navigation of chemical space. Acc. Chem. Res. 43, 1103–1114 (2010).

    Article  CAS  Google Scholar 

  6. Newman, D.J. & Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477 (2007).

    Article  CAS  Google Scholar 

  7. Carlson, E.E. Natural products as chemical probes. ACS Chem. Biol. 5, 639–653 (2010).

    Article  CAS  Google Scholar 

  8. Peterson, J.R. & Mitchison, T.J. Small molecules, big impact: a history of chemical inhibitors and the cytoskeleton. Chem. Biol. 9, 1275–1285 (2002).

    Article  CAS  Google Scholar 

  9. Islam, K. et al. A myosin V inhibitor based on privileged chemical scaffolds. Angew. Chem. Int. Ed. Engl. 49, 8484–8488 (2010).

    Article  CAS  Google Scholar 

  10. Mayer, T.U. et al. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286, 971–974 (1999).

    Article  CAS  Google Scholar 

  11. Orosz, F., Horváth, I. & Ovádi, J. New anti-mitotic drugs with distinct anti-calmodulin activity. Mini Rev. Med. Chem. 6, 1145–1157 (2006).

    Article  CAS  Google Scholar 

  12. Duflos, A., Kruczynski, A. & Barret, J.M. Novel aspects of natural and modified vinca alkaloids. Curr. Med. Chem. Anticancer Agents 2, 55–70 (2002).

    Article  CAS  Google Scholar 

  13. Tietze, L.F. Domino reactions in organic synthesis. Chem. Rev. 96, 115–136 (1996).

    Article  CAS  Google Scholar 

  14. Nicolaou, K.C. & Chen, J.S. The art of total synthesis through cascade reactions. Chem. Soc. Rev. 38, 2993–3009 (2009).

    Article  CAS  Google Scholar 

  15. Elders, N. et al. The efficient one-pot reaction of up to eight components by the union of multicomponent reactions. Angew. Chem. Int. Ed. Engl. 48, 5856–5859 (2009).

    Article  CAS  Google Scholar 

  16. Liu, W., Khedkar, V., Baskar, B., Schurmann, M. & Kumar, K. Branching cascades: a concise synthetic strategy targeting diverse and complex molecular frameworks. Angew. Chem. Int. Ed. Engl. 50, 6900–6905 (2011).

    Article  CAS  Google Scholar 

  17. Ishikura, M., Yamada, K. & Abe, T. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 27, 1630–1680 (2010).

    Article  CAS  Google Scholar 

  18. Lim, M.J. & Wang, X.W. Nucleophosmin and human cancer. Cancer Detect. Prev. 30, 481–490 (2006).

    Article  CAS  Google Scholar 

  19. Hutten, S. & Kehlenbach, R.H. CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol. 17, 193–201 (2007).

    Article  CAS  Google Scholar 

  20. Waldmann, H. et al. Asymmetric synthesis of natural product inspired tricyclic benzopyrones by an organocatalyzed annulation reaction. Angew. Chem. Int. Ed. Engl. 47, 6869–6872 (2008).

    Article  CAS  Google Scholar 

  21. Khedkar, V., Liu, W., Duckert, H. & Kumar, K. Efficient and atom-economic synthesis of α-substituted β-chromonyl-α,β-unsaturated carbonyls through molecular rearrangement. Synlett. 2010, 403–406; erratum 2010, 1576 (2010).

    Article  Google Scholar 

  22. Lavilla, R., Gotsens, T., Rodriguez, S. & Bosch, J. Studies on the nucleophilic-addition to 3,5-disubstituted pyridinium salts. Tetrahedron 48, 6445–6454 (1992).

    Article  CAS  Google Scholar 

  23. Wenkert, E. et al. General methods of synthesis of indole alkaloids. 14. Short routes of construction of yohimboid and ajmalicinoid alkaloid systems and their C-13 nuclear magnetic-resonance spectral analysis. J. Am. Chem. Soc. 98, 3645–3655 (1976).

    Article  CAS  Google Scholar 

  24. Hung, D.T., Jamison, T.F. & Schreiber, S.L. Understanding and controlling the cell cycle with natural products. Chem. Biol. 3, 623–639 (1996).

    Article  CAS  Google Scholar 

  25. Amin, M.A., Matsunaga, S., Uchiyama, S. & Fukui, K. Nucleophosmin is required for chromosome congression, proper mitotic spindle formation, and kinetochore-microtubule attachment in HeLa cells. FEBS Lett. 582, 3839–3844 (2008).

    Article  CAS  Google Scholar 

  26. Wang, W., Budhu, A., Forgues, M. & Wang, X.W. Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Nat. Cell Biol. 7, 823–830 (2005).

    Article  CAS  Google Scholar 

  27. Liu, Q., Jiang, Q. & Zhang, C. A fraction of Crm1 locates at centrosomes by its CRIME domain and regulates the centrosomal localization of pericentrin. Biochem. Biophys. Res. Commun. 384, 383–388 (2009).

    Article  CAS  Google Scholar 

  28. Plafker, K. & Macara, I.G. Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1. Mol. Cell Biol. 20, 3510–3521 (2000).

    Article  CAS  Google Scholar 

  29. Roberts, B.J., Hamelehle, K.L., Sebolt, J.S. & Leopold, W.R. In vivo and in vitro anticancer activity of the structurally novel and highly potent antibiotic CI-940 and its hydroxy analog (PD-114,721). Cancer Chemother. Pharmacol. 16, 95–101 (1986).

    Article  CAS  Google Scholar 

  30. Yashiroda, Y. & Yoshida, M. Nucleo-cytoplasmic transport of proteins as a target for therapeutic drugs. Curr. Med. Chem. 10, 741–748 (2003).

    Article  CAS  Google Scholar 

  31. Wulff, J.E., Siegrist, R. & Myers, A.G. The natural product avrainvillamide binds to the oncoprotein nucleophosmin. J. Am. Chem. Soc. 129, 14444–14451 (2007).

    Article  CAS  Google Scholar 

  32. Grisendi, S., Mecucci, C., Falini, B. & Pandolfi, P.P. Nucleophosmin and cancer. Nat. Rev. Cancer 6, 493–505 (2006).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research